Biphenyl compounds useful as muscarinic receptor antagonists

ABSTRACT

The invention provides compounds of formula I: 
                         
wherein a, b, c, m, n, q, r, W, Z 1 , Ar 1 , Z 2 , Y, R 1 , R 2 , and R 3  are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/660,435, filed on Mar. 10, 2005; the entire disclosure of which isincorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel biphenyl compounds havingmuscarinic receptor antagonist or anticholinergic activity. Theinvention also relates to pharmaceutical compositions comprising suchbiphenyl compounds, processes and intermediates for preparing suchbiphenyl compounds and methods of using such biphenyl compounds to treatpulmonary disorders.

2. State of the Art

Pulmonary or respiratory disorders, such as chronic obstructivepulmonary disease (COPD) and asthma, afflict many millions of peopleworldwide and such disorders are a leading cause of morbidity andmortality.

Muscarinic receptor antagonists are known to provide bronchoprotectiveeffects and therefore, such compounds are useful for treatingrespiratory disorders such as COPD and asthma. When used to treat suchdisorders, muscarinic receptor antagonists are typically administered byinhalation. However, even when administered by inhalation, a significantamount of the muscarinic receptor antagonist is often absorbed into thesystemic circulation resulting in systemic side effects such as drymouth, mydriasis and cardiovascular side effects.

Additionally, many inhaled muscarinic receptor antagonists have arelatively short duration of action requiring that they be administeredseveral times per day. Such a multiple-daily dosing regime is not onlyinconvenient but also creates a significant risk of inadequate treatmentdue to patient non-compliance with the required frequent dosingschedule.

Accordingly, a need exists for new muscarinic receptor antagonists. Inparticular, a need exists for new muscarinic receptor antagonists thathaving high potency and reduced systemic side effects when administeredby inhalation. Additionally, a need exists for inhaled muscarinicreceptor antagonists having a long duration of action thereby allowingfor once-daily or even once-weekly dosing. Such compounds are expectedto be particularly effective for treating pulmonary disorders, such asCOPD and asthma, while reducing or eliminating side effects such asdry-mouth and constipation.

SUMMARY OF THE INVENTION

The present invention provides novel biphenyl compounds havingmuscarinic receptor antagonist or anticholinergic activity. Among otherproperties, compounds of the invention are expected to possess highpotency and reduced systemic side effects when administered byinhalation and to have a long duration of action.

One aspect of the invention relates to a compound of formula I:

wherein:

a is 0 or an integer of from 1 to 5;

each R¹ is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g),—NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j),and R^(1k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R² is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(2a), —C(O)OR^(2b),—SR^(2c), —S(O)R^(2d), —S(O)₂R^(2c), —NR^(2f)R^(2g),—NR^(2h)S(O)₂R^(2i), and —NR^(2j)C(O)R^(2k); where each of R^(2a)R^(2b),R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j), andR^(2k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW^(a), where W^(a) is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R³ independently represents (1-4C)alkyl or two R³ groups are joinedto form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

Z¹ is selected from —C(O)N(R⁴)— and —N(R⁴)C(O)—, where R⁴ is selectedfrom hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

n is 0 or 1;

Ar¹ represents a phenylene group or a (3-5C)heteroarylene groupcontaining 1 or 2 heteroatoms independently selected from oxygen,nitrogen or sulfur; wherein the phenylene or heteroarylene group issubstituted with (R⁵)_(p) where p is 0 or an integer from 1 to 4 andeach R⁵ is independently selected from halo, hydroxy, (1-4C)alkyl or(1-4C)alkoxy;

q is 0 or 1;

Z² is selected from —C(O)N(R⁶)— and —N(R⁶)C(O)—, where R⁶ is selectedfrom hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

r is 0, 1 or 2;

Y is selected from

where:

R⁷ is selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl,—C(O)(1-4C)alkyl, -(1-4C)alkyleneC(O)OR^(7a), —C(O)heterocyclyl,—C(O)CH(NH₂)(1-4C)alkyleneQ, -(1-4C)alkyleneC(O)Q′,—C(O)(1-4C)alkyleneQ′, and —S(O)₂(1-4C)alkyleneQ′; where Q is anitrogen-containing substituent selected from —NR^(7b)R^(7c) andheteroaryl; Q′ is a nitrogen-containing substituent selected from—NR^(7d)R^(7e) and heterocyclyl; R^(7a) is hydrogen or (1-4C)alkyl; eachof R^(7b), R^(7c), R^(7d) and R^(7e) independently represents hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl or hydroxyphenyl, and where (1-4C)alkyl isunsubstituted or substituted by 1 or 2 substituents independentlyselected from amido, cyano, furyl, hydroxyl, and methylimidazolyl; theheterocyclyl contains 1 or 2 nitrogen atoms, and is unsubstituted orsubstituted by 1 or 2 substituents independently selected from hydroxyl,amido, (1-4C)alkoxy, oxo, —S(O)₂(1-4C)alkyl, —(CH₂)O(1-4C)alkyl,—(1-4C)alkyleneOH, —NR^(7f)R^(7g) and —C(O)NR^(7h)R^(7i), where each ofR^(7f), R^(7g) R^(7h) and R^(7i) independently represents hydrogen or(1-4C)alkyl; and the heteroaryl contains 1 or 2 nitrogen atoms;

X¹ is selected from (1-3C)alkylene, —C(O)(1-3C)alkylene,(1-3C)alkyleneC(O)—, —SO₂—, —SO₂(1-3C)alkylene and (1-3C)alkyleneSO₂—;where the alkylene group in any X¹ is optionally substituted with 1 or 2substituents independently selected from (1-4C)alkyl and —NR^(Xa)R^(Xb);wherein R^(Xa) and R^(Xb) are independently selected from hydrogen and(1-4 alkyl);

s is 0, 1 or 2;

each R⁸ independently represents (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, nitro, halo,N,N-di(1-4C)alkylamino(2-4C)alkoxy, —OR^(8a), —C(O)OR^(8b), —SR^(8c),—S(O)R^(8d), —S(O)₂R^(8e) or —NR^(8f)R^(8g); each of R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f) and R^(8g) is independently hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl, phenyl or phenyl(1-4C)alkyl, wherein eachphenyl group is unsubstituted or substituted by 1 or 2 substituentsindependently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;

R⁹ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkyleneNR^(9a)R^(9b),and phenyl, each of R^(9a) and R^(9b) is independently hydrogen or(1-4C)alkyl; or R⁹ is taken together with R⁸ to form a ring having 1 to2 oxygen atoms, where said ring is unsubstituted or substituted by 1 or2 (1-4C)alkyl substituents;

t is 0 or an integer from 1 to 3;

v is 0 or an integer from 1 to 4;

each R¹⁰ independently represents fluoro or (1-4C)alkyl;

R¹¹ is selected from hydrogen, —OH, -(1-4C)alkyleneOH,—C(O)NR^(11a)R^(11b), and —CH₂C(O)NR^(11a)R^(11b), where R^(11a) andR^(11b) are independently selected from hydrogen, (1-4C)alkyl, hydroxy,(1-4C)alkoxy, (1-4C)alkyleneOR^(11c), (3-6C)cycloalkyl, phenyloptionally substituted with hydroxy, and(−4C)alkyleneC(O)NR^(11d)R^(11e), where said (3-6C)cycloalkyl isunsubstituted or substituted with 1 or 2 (1-6C)alkyl or —NR^(11d)R^(11e)groups, and where each of R^(11c), R^(11d) and R^(11e) is independentlyhydrogen or (1-4C)alkyl; or R^(11a) is taken together with R^(11b) toform a 3-7 membered ring, optionally substituted with hydroxyl;

R¹² is selected from hydrogen, (1-4C)alkyl, -(1-4C)alkyleneOH, and-(1-4C)alkyleneheteroaryl; and

R¹³ is selected from (1-4C)alkyl, -(1-4C)alkyleneOH,-(1-4C)alkyleneheteroaryl, (3-6C)cycloalkyl,-(1-4C)alkylene(3-6C)cycloalkyl, and -(1-4C)alkyleneC(O)NR^(13a)R^(13b),where R^(13a) and R^(13b) are independently hydrogen or (1-4C)alkyl; orR¹² and R¹³ are taken together to form a ring selected frompiperazinone, morpholine, and piperazine; and said piperazine issubstituted with (R^(13c))_(w) where w is 0 or an integer from 1 to 3and each R^(13c) is independently selected from (1-4C)alkyl, phenyl orbenzyl, optionally substituted with 1 to 5 fluoro substituents, or twoR^(13c) groups are joined to form (1-3C)alkylene;

wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,R⁵, R⁸, R^(8a-8g), R⁹, and R^(9a-9b) is optionally substituted with 1 to5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomerthereof.

Another aspect of the invention relates to a compound of formula Ia:

where a, b, c, m, n, q, r, s, W, Ar¹, X¹, R¹⁻⁴ and R⁶⁻⁹ are as definedabove; or a pharmaceutically acceptable salt or solvate or stereoisomerthereof.

Another aspect of the invention relates to a compound of formula Ia′:

where a, b, c, m, n, q, r, W, Ar¹, R¹⁻⁴ and R⁶ are as defined above; ora pharmaceutically acceptable salt or solvate or stereoisomer thereof.

Another aspect of the invention relates to a compound of formula Ib:

where a, b, c, m, n, q, r, s, W, Ar¹, X¹, R¹⁻³ and R⁷⁻⁹ are as definedabove; Z^(1′) is —C(O)N(R⁴)— and Z^(2′) is selected from —C(O)N(R⁶)— and—N(R⁶)C(O)—; or Z^(1′) is —N(R⁴)C(O)— and Z^(2′) is —N(R⁶)C(O)—; or apharmaceutically acceptable salt or solvate or stereoisomer thereof.

Another aspect of the invention relates to a compound of formula Ic:

where a, b, c, m, n, q, r, W, Z¹, Ar¹, Z², and R¹⁻³ are as definedabove; Y′ is selected from

where t, v, and R¹⁰⁻¹³ are as defined above; or a pharmaceuticallyacceptable salt or solvate or stereoisomer thereof.

Another aspect of the invention pertains to a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of the invention or a pharmaceuticallyacceptable salt or solvate or stereoisomer thereof. Yet another aspectof the invention pertains to compositions comprising a compound of theinvention in combination with one or more other therapeutic agents.Accordingly, in one embodiment, the invention is directed to acomposition comprising (a) a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate or stereoisomer thereof; and(b) a therapeutically effective amount of an agent selected from asteroidal anti-inflammatory agent such as a corticosteroid; a β₂adrenergic receptor agonist; a phosphodiesterase-4 inhibitor; or acombination thereof; wherein the compound of the invention and the agentare formulated together or separately. When the agent is formulatedseparately, a pharmaceutically acceptable carrier may be included.

Compounds of the invention possess muscarinic receptor antagonistactivity, and are therefore expected to be useful for treating pulmonarydisorders such as chronic obstructive pulmonary disease and asthma.

Yet another aspect of the invention relates to a method for treating apulmonary disorder, comprising administering to a patient atherapeutically effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate or stereoisomer thereof.Still another aspect of the invention pertains to a method of producingbronchodilation in a patient, comprising administering to the patient abronchodilation-producing amount of a compound of the invention or apharmaceutically acceptable salt or solvate or stereoisomer thereof. Inone embodiment, the compound is administered by inhalation. Theinvention is also directed to a method of treating chronic obstructivepulmonary disease or asthma, comprising administering to a patient atherapeutically effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate or stereoisomer thereof.Another aspect of the invention relates to a method for antagonizing amuscarinic receptor in a mammal comprising administering to the mammal,a therapeutically effective amount of the compound of the invention.

Since compounds of the invention possess muscarinic receptor antagonistactivity, such compounds are also useful as research tools. Accordingly,another aspect of the invention is directed to a method for using acompound of the invention or a pharmaceutically acceptable salt orsolvate or stereoisomer thereof as a research tool for studying abiological system or sample, or for discovering new chemical compoundshaving muscarinic receptor antagonist activity.

The invention is also directed to processes and intermediates useful forpreparing compounds of the invention, and pharmaceutically acceptablesalts, solvates, and stereoisomers thereof. Accordingly, another aspectof the invention relates to a process of preparing a compound of theinvention (formula I, Ia-Ic or Ia′), comprising:

-   -   (a) reacting a compound of formula II with a compound of formula        III; or    -   (b) coupling a compound of formula IVa with a compound of        formula Va, or coupling a compound of formula IVb with a        compound of formula Vb; or    -   (c) coupling a compound of formula VIa with a compound of        formula VIIa, or coupling a compound of formula VIb with a        compound of formula VIIIb; or    -   (d) reacting a compound of formula VIII with a compound of        formula IX; or    -   (e) reacting a compound of formula II with a compound of formula        X in the presence of a reducing agent; or    -   (f) reacting a compound of formula XI with a compound of formula        IX in the presence of a reducing agent; and then removing any        protecting groups that may be present to provide a compound of        formula I, Ia-Ic or Ia′, and optionally, forming a        pharmaceutically acceptable salt thereof, wherein compounds of        formula I-XI are as defined herein.

In one embodiment, the above process further comprises the step offorming a pharmaceutically acceptable salt of a compound of formula I,Ia-Ic or Ia′. In other embodiments, the invention is directed to theother processes described herein; and to the product prepared by any ofthe processes described herein.

The invention is also directed to a compound of the invention or apharmaceutically acceptable salt or solvate or stereoisomer thereof, foruse in therapy or as a medicament.

Additionally, the invention is directed to the use of a compound of theinvention or a pharmaceutically acceptable salt or solvate orstereoisomer thereof, for the manufacture of a medicament; especiallyfor the manufacture of a medicament for the treatment of a pulmonarydisorder, for antagonizing a muscarinic receptor in a mammal, forproducing bronchodilation, or for treating chronic obstructive pulmonarydisease or asthma.

BRIEF DESCRIPTION OF THE DRAWINGS

Various aspects of the present invention are illustrated by reference tothe accompanying drawings.

FIG. 1 shows a powder x-ray diffraction (PXRD) pattern of a crystallinediacetate salt of biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester (the compound of Example 1). FIG. 2 shows a differential scanningcalorimetry (DSC) trace and a thermal gravimetric analysis (TGA) tracefor this crystalline salt.

FIG. 3 shows a PXRD pattern of a crystalline monooxalate salt of thecompound of Example 1.

DSC and TGA traces for this crystalline salt are shown in FIG. 4.

FIG. 5 shows a PXRD pattern of a crystalline dipropionate salt of thecompound of Example 1.

DSC and TGA traces for this crystalline salt are shown in FIG. 6.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to novel biphenyl compounds of formula I, andpharmaceutically acceptable salts, solvates or stereoisomers thereof.Compounds of formula I of particular interest include those compoundshaving formula Ia, Ib and Ic. The invention is also directed to novelbiphenyl compounds of formula Ia′, and pharmaceutically acceptablesalts, solvates or stereoisomers thereof. Compounds of formula Ia′ areuseful as intermediates in the synthesis of compounds of formula Ia.Further, compounds of formula Ia′ may be metabolites of compounds offormula Ia, and more particularly, may be active metabolites ofcompounds of formula Ia.

The compounds of the invention may contain one or more chiral centersand therefore, the invention is directed to racemic mixtures; purestereoisomers (i.e., enantiomers or diastereomers);stereoisomer-enriched mixtures and the like unless otherwise indicated.When a particular stereoisomer is shown or named herein, it will beunderstood by those skilled in the art that minor amounts of otherstereoisomers may be present in the compositions of the invention unlessotherwise indicated, provided that the desired utility of thecomposition as a whole is not eliminated by the presence of such otherisomers.

The compounds of the invention also contain several basic groups (e.g.,amino groups) and therefore, can exist as the free base or in varioussalt forms. All such salt forms are included within the scope of theinvention. Furthermore, solvates of compounds of the invention or saltsthereof are included within the scope of the invention. Additionally,where applicable, all cis-trans or E/Z isomers (geometric isomers),tautomeric forms and topoisomeric forms of the compounds of theinvention are included within the scope of the invention unlessotherwise specified.

The compounds of the invention, as well as those compounds used in theirsynthesis, may also include isotopically-labeled compounds, i.e., whereone or more atoms have been enriched with atoms having an atomic massdifferent from the atomic mass predominately found in nature. Examplesof isotopes that may be incorporated into the compounds of the inventioninclude, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O and ¹⁷O.

The nomenclature used herein to name the compounds of the invention isillustrated in the Examples herein. This nomenclature has been derivedusing the commercially-available AutoNom software (MDL, San Leandro,Calif.). For example, compounds of formulas I, Ia-Ic and Ia′, where W isO have typically been named as ester derivatives ofbiphenyl-2-ylcarbamic acid.

Representative Embodiments

The following substituents and values for compounds of the invention(formulas I, Ia-Ic, and Ia′), are intended to provide representativeexamples of various aspects and embodiments of the invention. Theserepresentative values are intended to further define and illustrate suchaspects and embodiments and are not intended to exclude otherembodiments or to limit the scope of the invention. In this regard, therepresentation that a particular value or substituent is preferred isnot intended in any way to exclude other values or substituents from theinvention unless specifically indicated.

One embodiment of the invention pertains to compounds of formula I,where Z¹ is —N(R⁴)C(O)—, Z² is —C(O)N(R⁶)—, and Y is:

These compounds have the following formula Ia:

wherein:

a is 0 or an integer of from 1 to 5;

each R¹ is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g),—NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j),and R^(1k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R² is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(2a), —C(O)OR^(2b),—SR^(2c), —S(O)R^(2d), —S(O)₂R^(2e), —NR^(2f)R^(2g),—NR^(2h)S(O)₂R^(2i), and —NR^(2j)C(O)R^(2k); where each of R^(2a)R^(2b),R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j), andR^(2k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW^(a), where W^(a) is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R³ independently represents (1-4C)alkyl or two R³ groups are joinedto form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

R⁴ is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

n is 0 or 1;

Ar¹ represents a phenylene group or a (3-5C)heteroarylene groupcontaining 1 or 2 heteroatoms independently selected from oxygen,nitrogen or sulfur; wherein the phenylene or heteroarylene group issubstituted with (R⁵)_(p) where p is 0 or an integer from 1 to 4 andeach R⁵ is independently selected from halo, hydroxy, (1-4C)alkyl or(1-4C)alkoxy;

q is 0 or 1;

R⁶ is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

r is 0, 1 or 2;

R⁷ is selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl,—C(O)(1-4C)alkyl, -(1-4C)alkyleneC(O)OR^(7a), —C(O)heterocyclyl,—C(O)CH(NH₂)(1-4C)alkyleneQ, -(1-4C)alkyleneC(O)Q′,—C(O)(1-4C)alkyleneQ′, and —S(O)₂(1-4C)alkyleneQ′; where Q is anitrogen-containing substituent selected from —NR^(7b)R^(7c) andheteroaryl; Q′ is a nitrogen-containing substituent selected from—NR^(7d)R^(7e) and heterocyclyl; R^(7a) is hydrogen or (1-4C)alkyl; eachof R^(7b), R^(7c), R^(7d) and R^(7e) independently represents hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl or hydroxyphenyl, and where (1-4C)alkyl isunsubstituted or substituted by 1 or 2 substituents independentlyselected from amido, cyano, furyl, hydroxyl, and methylimidazolyl; theheterocyclyl contains 1 or 2 nitrogen atoms, and is unsubstituted orsubstituted by 1 or 2 substituents independently selected from hydroxyl,amido, (1-4C)alkoxy, oxo, —S(O)₂(1-4C)alkyl, —(CH₂)O(1-4C)alkyl,-(1-4C)alkyleneOH, —NR^(7f)R^(7g) and —C(O)NR^(7h)R^(7i), where each ofR^(7f), R^(7g) R^(7h) and R^(7i) independently represents hydrogen or(1-4C)alkyl; and the heteroaryl contains 1 or 2 nitrogen atoms;

X¹ is selected from (1-3C)alkylene, —C(O)(1-3C)alkylene,(1-3C)alkyleneC(O)—, —SO₂—, —SO₂(1-3C)alkylene and (1-3C)alkyleneSO₂—;where the alkylene group in any X¹ is optionally substituted with 1 or 2substituents independently selected from (1-4C)alkyl and —NR^(Xa)R^(Xb);wherein R^(Xa) and R^(Xb) are independently selected from hydrogen and(1-4 alkyl);

s is 0, 1 or 2;

each R⁸ independently represents (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, nitro, halo,N,N-di(1-4C)alkylamino(2-4C)alkoxy, —OR^(8a), —C(O)OR^(8b), —SR^(8c),—S(O)R^(8d), —S(O)₂R^(8e) or ——NR^(8f)R^(8g); each of R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f) and R^(8g) is independently hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl, phenyl or phenyl(1-4C)alkyl, wherein eachphenyl group is unsubstituted or substituted by 1 or 2 substituentsindependently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;

R⁹ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkyleneNR^(9a)R^(9b),and phenyl, each of R^(9a) and R^(9b) is independently hydrogen or(1-4C)alkyl; or R⁹ is taken together with R⁸ to form a ring having 1 to2 oxygen atoms, where said ring is unsubstituted or substituted by 1 or2 (1-4C)alkyl substituents; and

wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,R⁵, R⁸, R^(8a-8g), R⁹, and R^(9a-9b) is optionally substituted with 1 to5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomerthereof.

Exemplary a, b, c, m, n, q, r, and s values, and exemplary W, Ar¹, X¹,R¹⁻⁴, and R⁶⁻⁹ substituents are as described below.

Another aspect of the invention relates to a compound of formula Ia′:

wherein:

a is 0 or an integer of from 1 to 5;

each R¹ is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g),—NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j),and R^(1k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R² is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(2a), —C(O)OR^(2b),—SR^(2c), —S(O)R^(2d), —S(O)₂R^(2e), ——NR^(2f)R^(2g),—NR^(2h)S(O)₂R^(2i), and —NR^(2j)C(O)R^(2k); where each of R^(2a)R^(2b),R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j), andR^(2k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW^(a), where W^(a) is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R³ independently represents (1-4C)alkyl or two R³ groups are joinedto form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

R⁴ is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

n is 0 or 1;

Ar¹ represents a phenylene group or a (3-5C)heteroarylene groupcontaining 1 or 2 heteroatoms independently selected from oxygen,nitrogen or sulfur; wherein the phenylene or heteroarylene group issubstituted with (R⁵)_(p) where p is 0 or an integer from 1 to 4 andeach R⁵ is independently selected from halo, hydroxy, (1-4C)alkyl or(1-4C)alkoxy;

q is 0 or 1;

R⁶ is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

r is 0, 1 or 2;

wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,and R⁵ is optionally substituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomerthereof.

Exemplary a, b, c, m, n, q, and r values, and exemplary W, Ar¹, R¹⁻⁴ andR⁶ substituents are as described below.

Another embodiment of the invention pertains to compounds of formula I,where Z¹ is —C(O)N(R⁴)— and Z² is selected from —C(O)N(R⁶)— and—N(R⁶)C(O)—, or Z¹ is —N(R⁴)C(O)— and Z² is —N(R⁶)C(O)—; and Y is:

These compounds have the following formula Ib:

wherein:

a is 0 or an integer of from 1 to 5;

each R¹ is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g),—NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j),and R^(1k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R² is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(2a), —C(O)OR^(2b),—SR^(2c), —S(O)R^(2d), —S(O)₂R^(2e), —NR^(2f)R^(2g),—NR^(2h)S(O)₂R^(2i), and —NR^(2j)C(O)R^(2k); where each of R^(2a),R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j),and R^(2k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW^(a), where W^(a) is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R³ independently represents (1-4C)alkyl or two R³ groups are joinedto form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

Z^(1′) is —C(O)N(R⁴)— and Z^(2′) is selected from —C(O)N(R⁶)— and—N(R⁶)C(O)—; or Z^(1′) is —N(R⁴)C(O)— and Z^(2′) is —N(R⁶)C(O)—;

R⁴ is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

R⁶ is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

n is 0 or 1;

Ar¹ represents a phenylene group or a (3-5C)heteroarylene groupcontaining 1 or 2 heteroatoms independently selected from oxygen,nitrogen or sulfur; wherein the phenylene or heteroarylene group issubstituted with (R⁵)_(p) where p is 0 or an integer from 1 to 4 andeach R⁵ is independently selected from halo, hydroxy, (1-4C)alkyl or(1-4C)alkoxy;

q is 0 or 1;

r is 0, 1 or 2;

R⁷ is selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl,—C(O)(1-4C)alkyl, -(1-4CalkyleneC(O)OR^(7a), —C(O)heterocyclyl,—C(O)CH(NH₂)(1-4C)alkyleneQ, -(1-4C)alkyleneC(O)Q′,—C(O)(1-4C)alkyleneQ′, and —S(O)₂(1-4C)alkyleneQ′; where Q is anitrogen-containing substituent selected from —NR^(7b)R^(7c) andheteroaryl; Q′ is a nitrogen-containing substituent selected from—NR^(7d)R^(7e) and heterocyclyl; R^(7a) is hydrogen or (1-4C)alkyl; eachof R^(7b), R^(7c), R^(7d) and R^(7e) independently represents hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl or hydroxyphenyl, and where (1-4C)alkyl isunsubstituted or substituted by 1 or 2 substituents independentlyselected from amido, cyano, furyl, hydroxyl, and methylimidazolyl; theheterocyclyl contains 1 or 2 nitrogen atoms, and is unsubstituted orsubstituted by 1 or 2 substituents independently selected from hydroxyl,amido, (1-4C)alkoxy, oxo, —S(O)₂(1-4C)alkyl, —(CH₂)O(1-4C)alkyl,-(1-4C)alkyleneOH, —NR^(7f)R^(7g) and —C(O)NR^(7h)R^(7i), where each ofR^(7f), R^(7g) R^(7h) and R^(7i) independently represents hydrogen or(1-4C)alkyl; and the heteroaryl contains 1 or 2 nitrogen atoms;

X¹ is selected from (1-3C)alkylene, —C(O)(1-3C)alkylene,(1-3C)alkyleneC(O)—, —SO₂—, —SO₂(1-3C)alkylene and (1-3C)alkyleneSO₂—;where the alkylene group in any X¹ is optionally substituted with 1 or 2substituents independently selected from (1-4C)alkyl and —NR^(Xa)R^(Xb);wherein R^(Xa) and R^(Xb) are independently selected from hydrogen and(1-4alkyl);

s is 0, 1 or 2;

each R⁸ independently represents (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, nitro, halo,N,N-di(1-4C)alkylamino(2-4C)alkoxy, —OR^(8a), —C(O)OR^(8b), —SR^(8c),—S(O)R^(8d), —S(O)₂R^(8e) or —NR^(8f)R^(8g); each of R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f) and R^(8g) is independently hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl, phenyl or phenyl(1-4C)alkyl, wherein eachphenyl group is unsubstituted or substituted by 1 or 2 substituentsindependently selected from halo, (1-4C)alkyl and (1-4C)alkoxy;

R⁹ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkyleneNR^(9a)R^(9b),and phenyl, each of R^(9a) and R^(9b) is independently hydrogen or(1-4C)alkyl; or R⁹ is taken together with R⁸ to form a ring having 1 to2 oxygen atoms, where said ring is unsubstituted or substituted by 1 or2 (1-4C)alkyl substituents; and

wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,R⁵, R⁸, R^(8a-8g), R⁹, and R^(9a-9b) is optionally substituted with 1 to5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomerthereof.

Exemplary a, b, c, m, n, q, r and s values, and exemplary W, Ar¹, X¹,R¹⁻⁴ , and R⁶⁻⁹ substituents are as described below.

Yet another embodiment of the invention pertains to compounds of formulaI, where Y selected from

These compounds have the following formula Ic:

wherein:

a is 0 or an integer of from 1 to 5;

each R¹ is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g),—NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j),and R^(1k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R² is independently selected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR^(2a), —C(O)OR^(2b),—SR^(2c), S(O)R^(2d), —S(O)₂R^(2e), —NR^(2f)R^(2g), —NR^(2h)S(O)₂R^(2i),and —NR^(2j)C(O)R^(2k); where each of R^(2a), R^(2b), R^(2c), R^(2d),R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j), and R^(2k) isindependently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW^(a), where W^(a) is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R³ independently represents (1-4C)alkyl or two R³ groups are joinedto form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

Z¹ is selected from —C(O)N(R⁴)— and —N(R⁴)C(O)—, where R⁴ is selectedfrom hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

n is 0 or 1;

Ar¹ represents a phenylene group or a (3-5C)heteroarylene groupcontaining 1 or 2 heteroatoms independently selected from oxygen,nitrogen or sulfur; wherein the phenylene or heteroarylene group issubstituted with (R⁵)_(p) where p is 0 or an integer from 1 to 4 andeach R⁵ is independently selected from halo, hydroxy, (1-4C)alkyl or(1-4C)alkoxy;

q is 0 or 1;

Z² is selected from —C(O)N(R⁶)— and —N(R⁶)C(O)—, where R⁶ is selectedfrom hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

r is 0, 1 or 2;

Y′ is selected from

where:

t is 0 or an integer from 1 to 3;

v is 0 or an integer from 1 to 4;

each R¹⁰ independently represents fluoro or (1-4C)alkyl;

R¹¹ is selected from hydrogen, —OH, -(1-4C)alkyleneOH,—C(O)NR^(11a)R^(11b), and —CH₂C(O)NR^(11a)R^(11b), where R^(11a) andR^(11b) are independently selected from hydrogen, (1-4C)alkyl, hydroxy,(1-4C)alkoxy, (1-4C)alkyleneOR^(11c), (3-6C)cycloalkyl, phenyloptionally substituted with hydroxy, and(1-4C)alkyleneC(O)NR^(11d)R^(11e), where said (3-6C)cycloalkyl isunsubstituted or substituted with 1 or 2 (1-6C)alkyl or —NR^(11d)R^(11e)groups, and where each of R^(11c), R^(11d) and R^(11e) is independentlyhydrogen or (1-4C)alkyl; or R^(11a) is taken together with R^(11b) toform a 3-7 membered ring, optionally substituted with hydroxyl;

R¹² is selected from hydrogen, (1-4C)alkyl, -(1-4C)alkyleneOH, and-(1-4C)alkyleneheteroaryl; and

R¹³ is selected from (1-4C)alkyl, -(1-4C)alkyleneOH,-(1-4C)alkyleneheteroaryl, (3-6C)cycloalkyl,-(1-4C)alkylene(3-6C)cycloalkyl, and -(1-4C)alkyleneC(O)NR^(13a)R^(13b),where R^(13a) and R^(13b) are independently hydrogen or (1-4C)alkyl; orR¹² and R¹³ are taken together to form a ring selected frompiperazinone, morpholine, and piperazine; and said piperazine issubstituted with (R^(13c))^(w) where w is 0 or an integer from 1 to 3and each R^(13c) is independently selected from (1-4C)alkyl, phenyl orbenzyl, optionally substituted with 1 to 5 fluoro substituents, or twoR^(13c) groups are joined to form (1-3C)alkylene;

wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,and R⁵ is optionally substituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or solvate or stereoisomerthereof.

Exemplary a, b, c, m, n, q, r, t and v values, and exemplary W, Z¹, Ar¹,Z², Y, R¹⁻³, and R¹⁰⁻¹³ substituents are as described below.

Unless specified otherwise, the following discussion relates to theintegers and substituents present in compounds having formulas I, Ia,Ib, Ic, and Ia′, as well as in the formulas of compounds discussed inthe general synthetic procedures section.

The value for a is 0, 1, 2, 3, 4 or 5; particularly 0, 1 or 2, and evenmore particularly 0 or 1. The value for b is 0, 1, 2, 3 or 4;particularly 0, 1 or 2, and even more particularly 0 or 1. In oneembodiment, a is 0. In another embodiment, b is zero. In yet anotherembodiment, both a and b are 0.

When present, each R¹ may be at the 2, 3, 4, 5 or 6-position of thephenyl ring to which it is attached. Each R¹ is independently selectedfrom (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano,halo, —OR^(1a), —C(O)OR^(1b), —SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e),—NR^(1f)R^(1g), —NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k), examples ofwhich include methyl, fluoro, chloro, bromo, hydroxy, methoxy, amino,methylamino, dimethylamino and the like. Particular values for R¹ arefluoro or chloro.

When present, each R² may be at the 3, 4, 5 or 6-position on thephenylene ring to which it is attached (where the carbon atom on thephenylene ring attached to the nitrogen atom is position 1). Each R² isindependently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,(3-6C)cycloalkyl, cyano, halo, —OR^(2a), —C(O)OR^(2b), —SR^(2c),—S(O)R^(2d), —S(O)₂R^(2e), —NR^(2f)R^(2g), —NR^(2h)S(O)₂R^(2i), and—NR^(2j)C(O)R^(2k), examples of which include methyl, fluoro, chloro,bromo, hydroxy, methoxy, amino, methylamino, dimethylamino and the like.Particular values for R² are fluoro or chloro.

Each R^(1a-1k) and R^(2a-2k) group as used in R¹ and R², respectively,is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl, examples ofwhich include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl or benzyl. In one embodiment, thesegroups are independently hydrogen or (1-3C)alkyl. In another embodiment,these groups are independently hydrogen, methyl or ethyl. In addition,each alkyl and alkoxy group in R¹, R^(1a-1k), R², and R^(2a-2k) isoptionally substituted with 1 to 5 fluoro substituents.

W can be O or NW^(a). Generally, it has been found that compounds inwhich W represents O exhibit particularly high affinity for muscarinicreceptors. Accordingly, in a particular embodiment of the invention, Wrepresents O.

When W is NW^(a), W^(a) is hydrogen or (1-4C)alkyl, examples of whichinclude hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl and tert-butyl. In one embodiment, W^(a) is hydrogenor (1-3C)alkyl. In another embodiment, W^(a) is hydrogen, methyl orethyl, particularly hydrogen or methyl. In yet another embodiment, W^(a)is hydrogen.

The value for c is 0, 1, 2, 3, 4, or 5; particularly 0, 1, or 2; andmore particularly 0 or 1. In one particular embodiment, c is 0. Inanother embodiment, c is 2.

In one embodiment, each R³ is at the 3, 4 or 5-position on thepiperidine ring (where the nitrogen atom of the piperidine ring isposition 1). In a particular embodiment, R³ is at 4-position on thepiperidine ring. In another embodiment, R³ is at the 1-position of thepiperidine ring, i.e., on the nitrogen atom of the piperidine ring thusforming a quaternary amine salt. Each R³ is independently (1-4C)alkyl,or two R³ groups are joined to form (1-3C)alkylene, (2-3C)alkenylene oroxiran-2,3-diyl. In one embodiment, each R³ is independently (1-4C)alkylsuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyland tert-butyl. In addition, each alkyl group in R³ is optionallysubstituted with 1 to 5 fluoro substituents. In one embodiment, each R³is independently (1-3C) alkyl, and in another embodiment, each R³ isindependently methyl or ethyl.

In yet another embodiment, two R³ groups are joined to form a(1-3C)alkylene or (2-3C)alkenylene group. For example, two R³ groups atthe 2 and 6-positions on the piperidine ring can be joined to form anethylene bridge (i.e., the piperidine ring and the R³ groups form an8-azabicyclo[3.2.1]octane ring); or two R³ groups at the 1 and4-positions on the piperidine ring can be joined to form an ethylenebridge (i.e., the piperidine ring and the R³ groups form an1-azabicyclo[2.2.2]octane ring). In this embodiment, other R³ groups asdefined herein may also be present.

In still another embodiment, two R³ groups are joined to form aoxiran-2,3-diyl group. For example, two R³ groups at the 2 and6-positions on the piperidine ring can be joined to form a3-oxatricyclo[3.3.1.0^(2,4)]nonane ring). In this embodiment, other R³groups as defined herein may also be present.

The value for m is 0 or 1. In one embodiment, m is 0.

In the compounds of formulas I and Ic, Z¹ is —C(O)N(R⁴)— or —N(R⁴)C(O)—,while in the compound of formula Ib, Z¹ is —C(O)N(R⁴)— or —N(R⁴)C(O)—.R⁴ in formulas I, Ia-c and Ia′, represents hydrogen, (1-4C)alkyl, or(3-4C)cycloalkyl. Examples of (1-4C)alkyl include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl.Examples of (3-4C)cycloalkyl groups include cyclopropyl and cyclobutyl.In one embodiment R⁴ represents hydrogen or (1-4C)alkyl, in particularhydrogen or methyl. In another embodiment, R⁴ is hydrogen. In oneparticular embodiment, Z¹ is —N(R⁴)C(O)—.

The value for n is 0 or 1. A particular value for n is 0.

Ar¹ is a phenylene group or a (3-5C)heteroarylene group containing 1 or2 heteroatoms independently selected from oxygen, nitrogen or sulfur.The value for p is 0, 1, 2, 3, or 4, particularly 0, 1, 2 or 3. In oneembodiment, p is 0, 1 or 2. Thus, the phenylene or heteroarylene groupmay be unsubstituted (p is 0) or substituted with 1 to 4 R⁵substituents, which are independently selected from halo, hydroxy,(1-4C)alkyl or (1-4C)alkoxy. In addition, each alkyl and alkoxy group inR⁵ is optionally substituted with 1 to 5 fluoro substituents. The pointof attachment for Ar¹ is at any available carbon or heteroatom ringatom. In certain embodiments, Ar¹ is a phenylene group attached at themeta or para position.

In one embodiment Ar¹ is phen-1,3-ylene or phen-1,4-ylene wherein thephenylene group is unsubstituted or substituted with 1, 2 or 3 R⁵substituents. Representative R⁵ substituents include fluoro, chloro,bromo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, methoxy, ethoxy, isopropoxy, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl and trifluoromethoxy. Particularexamples of Ar¹ groups in this embodiment include2-fluorophen-1,4-ylene, 3-fluorophen-1,4-ylene, 2-chlorophen-1,4-ylene,3-chlorophen-1,4-ylene, 2-methylphen-1,4-ylene, 3-methylphen-1,4-ylene,2-methoxyphen-1,4-ylene, 3-methoxyphen-1,4-ylene,2-trifluoromethoxyphen-1,4-ylene, 3-trifluoromethoxyphen-1,4-ylene,2,3-difluorophen-1,4-ylene, 2,5-difluorophen-1,4-ylene,2,6-difluorophen-1,4-ylene, 2,3-dichlorophen-1,4-ylene,2,5-dichlorophen-1,4-ylene, 2,6-dichlorophen-1,4-ylene,2-chloro-5-methoxyphen-1,4-ylene, 2-chloro-6-methoxyphen-1,4-ylene,2-chloro-5-trifluoromethoxyphen-1,4-ylene,2-chloro-6-trifluoromethoxyphen-1,4-ylene, and2,5-dibromophen-1,4-ylene.

In another embodiment, Ar¹ is a (3-5C)heteroarylene group containing 1or 2 heteroatoms independently selected from oxygen, nitrogen andsulfur; wherein the heteroarylene group is unsubstituted or substitutedwith 1 or 2 R⁵ substituents. Representative heteroarylene groups includedivalent species of pyrrole, imidazole, thiazole, oxazole, furan,thiophene, pyrazole, isoxazole, isothiazole, pyridine, pyrazine,pyridazine and pyrimidine, where the point of attachment is at anyavailable carbon or nitrogen ring atom. More specific examples of suchAr¹ groups include 2,5-furylene, 2,4-thienylene, 2,5-thienylene,2,5-pyridylene, 2,6-pyridylene, 3,5-pyridylene and 2,5-pyrrolylene.Representative R⁵ substituents include fluoro, chloro, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy,ethoxy, isopropoxy, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl and trifluoromethoxy. Particular examples ofsubstituted Ar¹ groups include 3-fluoro-2,5-thienylene,3-chloro-2,5-thienylene, 3-methyl-2,5-thienylene,3-methoxy-2,5-thienylene, and 3-methoxy-6-chloro-2,5-pyridylene.

In one particular embodiment, Ar¹ represents phen-1,3-ylene,phen-1,4-ylene, 2,4-thienylene or 2,5-thienylene; wherein the phenyleneor thienylene group is optionally substituted with 1 or 2 R⁵substituents. In another particular embodiment, Ar¹ representsphen-1,3-ylene or 2,5-thienylene optionally substituted with 1 or 2 R⁵substituents.

The value for q is 0 or 1. A particular value for q is 0.

In the compounds of formulas I and Ic, Z² is —C(O)N(R⁶)— or —N(R⁶)C(O)—,while in the compound of formula Ib, Z^(2′) is —C(O)N(R⁶)— or—N(R⁶)C(O)—. R⁶ in formulas I, Ia-c and Ia′, represents hydrogen,(1-4C)alkyl, or (3-4C)cycloalkyl. Examples of (1-4C)alkyl includemethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl andtert-butyl. Examples of (3-4C)cycloalkyl groups include cyclopropyl andcyclobutyl. In one embodiment R⁶ represents hydrogen or (1-4C)alkyl, inparticular hydrogen or methyl. In another embodiment, R⁶ is hydrogen. Inone particular embodiment, Z² is —C(O)N(R⁶)—.

The value for r is 0, 1, or 2. In one embodiment, r is 0. In anotherembodiment, r is 1.

In compounds of formula I, Y is selected from

In one particular embodiment or formula I, and in the embodiment offormulas Ia and Ib, Y is

R⁷ represents hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl, —C(O)(1-4C)alkyl,(1-4C)alkyleneC(O)OR^(7a), —C(O)heterocyclyl,—C(O)CH(NH₂)(1-4C)alkyleneQ, -(1-4C)alkyleneC(O)Q′,—C(O)(1-4C)alkyleneQ′, or —S(O)₂(1-4C)alkyleneQ′. Q is anitrogen-containing substituent selected from —NR^(7b)R^(7c) andheteroaryl. Q′ is a nitrogen-containing substituent selected from—NR^(7d)R^(7e) and heterocyclyl. R^(7a) is hydrogen or (1-4C)alkyl. Eachof R^(7b), R^(7c), R^(7d) and R^(7e) independently represents hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl or hydroxyphenyl, and (1-4C)alkyl isunsubstituted or substituted by 1 or 2 substituents independentlyselected from amido, cyano, furyl, hydroxyl, and methylimidazolyl. Theheterocyclyl contains 1 or 2 nitrogen atoms, and is unsubstituted orsubstituted by 1 or 2 substituents independently selected from hydroxyl,amido, (1-4C)alkoxy, oxo, —S(O)₂(1-4C)alkyl, —(CH₂)O(1-4C)alkyl,-(1-4C)alkyleneOH, —NR^(7f)R^(7g) and —C(O)NR^(7h)R^(7i), where each ofR^(7f), R^(7g) R^(7h) and R^(7i) independently represents hydrogen or(1-4C)alkyl. The heteroaryl contains 1 or 2 nitrogen atoms. Theheterocyclyl and heteroaryl groups may contain other heteroatoms, inaddition to the 1 or 2 nitrogen atoms. For example the heterocyclyl canbe a morpholinyl group.

In one embodiment, R⁷ represents hydrogen, (1-4C)alkyl, or(3-4C)cycloalkyl, examples of which include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl andcyclobutyl. In another embodiment, R⁷ represents hydrogen or(1-3C)alkyl, particularly methyl. In another particular embodiment, R⁷is methyl. In yet another embodiment, R⁷ is hydrogen.

In one embodiment, R⁷ is —C(O)(1-4C)alkyl. Particular embodimentsinclude where R⁷ is —C(O)CH₃ and —C(O)CH₂CH₃.

In another embodiment, R⁷ is —(1-4C)alkyleneC(O)OR^(7a). In particularembodiments, R⁷ is —(CH₂)₂C(O)OH or —(CH₂)₂C(O)OCH₃.

In yet another embodiment, R⁷ is —C(O)heterocyclyl. In a particularembodiment, the heterocyclyl contains 1 nitrogen atom, and isunsubstituted or substituted with a hydroxyl. Particular embodimentsinclude where the heterocyclyl is pyrrolidinyl, hydroxypyrrolidinyl orpiperidyl.

In another embodiment, R⁷ is —C(O)CH(NH₂)(1-4C)alkyleneQ. In oneparticular embodiment, Q is —NR^(7b)R^(7c) such as —NH₂. In anotherembodiment, Q is a heteroaryl such as pyridyl or imidazolyl.

In a particular embodiment, R⁷ is -(1-4C)alkyleneC(O)Q′, where Q′ is—NR^(7d)R^(7e), for example —(CH₂)₂C(O)NR^(7d)R^(7e). In one embodiment,R^(7d) and R^(7e) are both (1-4C)alkyl, and methyl in particular. Inanother embodiment, R^(7d) is hydrogen and R^(7e) is selected from(1-4C)alkyl (such as methyl and ethyl), (3-6C)cycloalkyl (such ascyclopropyl) and hydroxyphenyl. In one embodiment, the (1-4C)alkyl isunsubstituted or substituted with furyl, hydroxyl or methylimidazolyl.

In a particular embodiment, R⁷ is -(1-4C)alkyleneC(O)Q′, where Q′ is aheterocyclyl, for example —(CH₂)₂C(O)heterocyclyl. In one embodiment,the heterocyclyl contains 1 nitrogen atom such as piperidyl, and issubstituted with an amido.

In still another embodiment, R⁷ is —C(O)(1-4C)alkyleneQ′, where Q′ is—NR^(7d)R^(7e), for example —C(O)CH₂NR^(7d)R^(7e),—C(O)(CH₂)₂NR^(7d)R^(7e), and —C(O)(CH₂)₃NR^(7d)R^(7e). In a particularembodiment, each of R^(7d) and R^(7e) independently represents hydrogen,or (1-4C)alkyl. In another embodiment, R^(7d) is hydrogen or methyl andR^(7e) is (1-4C)alkyl substituted with amido, cyano, furyl, or hydroxyl.

In still another embodiment, R⁷ is —C(O)(1-4C)alkyleneQ′, where Q′ is aheterocyclyl such as —C(O)(CH₂)heterocyclyl, —C(O)(CH₂)₂heterocyclyl and—C(O)(CH₂)₃heterocyclyl. In one embodiment, the heterocyclyl contains 1nitrogen atom such as pyrrolidinyl or piperidyl. In another embodiment,the heterocyclyl contains 2 nitrogen atoms such as piperazinyl,tetrahydropyrimidinyl and 1,4 diazepanyl. In a particular embodiment,the heterocyclyl is pyrrolidinyl, unsubstituted or substituted withamido or (1-4C)alkoxy such as methoxy. In a particular embodiment, theheterocyclyl is piperidyl unsubstituted or substituted by 1 or 2substituents independently selected from hydroxyl, amido, and(1-4C)alkoxy such as methoxy. In a particular embodiment, theheterocyclyl is tetrahydropyrimidinyl substituted with oxo. In anotherparticular embodiment, the heterocyclyl is piperazinyl substituted with—S(O)₂(1-4C)alkyl such as —S(O)₂CH₂CH₃. In yet another embodiment, theheterocyclyl is 1,4 diazepanyl substituted with oxo.

In yet another embodiment, R⁷ is —S(O)₂(1-4C)alkyleneQ′, where Q′ is—NR^(7d)R^(7e) such as —S(O)₂(CH₂)₂NR^(7d)R^(7e). In a particularembodiment each of R^(7d) and R^(7e) independently represents(1-4C)alkyl, where (1-4C)alkyl is substituted with hydroxyl, for example—N(CH₂CH₂OH)₂.

In yet another embodiment, R⁷ is —S(O)₂(1-4C)alkyleneQ′, where Q′ is aheterocyclyl such as —S(O)₂(CH₂)₂ heterocyclyl. In a particularembodiment, the heterocyclyl is piperidyl substituted with hydroxyl,-(1-4C)alkyleneOH such as —(CH₂)₂OH, or —C(O)NR^(7h)R^(7i) such as—(CO)N(CH₂CH₃)₂. In another embodiment, the heterocyclyl is piperazinyl,substituted with oxo.

X¹ is selected from (1-3C)alkylene, —C(O)(1-3C)alkylene,(1-3C)alkyleneC(O)—, —SO₂—, —SO₂(1-3C)alkylene and (1-3C)alkyleneSO₂—.The alkylene group in any X¹ is optionally substituted with 1 or 2substituents independently selected from (1-4C)alkyl and —NR^(Xa)R^(Xb),where R^(Xa) and R^(Xb) are independently selected from hydrogen and(1-4alkyl). In one embodiment, X¹ is selected from (1-3C)alkylene,—C(O)(1-3C)alkylene, (1-3C)alkyleneC(O)— or —SO₂—. Examples ofparticular values for X¹ are —CH₂—, —CH₂CH₂—, —CH₂C(O)—,—C(O)CH(NH₂)CH₂— and —SO₂—. In a particular embodiment, X¹ is —CH₂— or—CH₂CH₂—.

The value for s is 0, 1, or 2. Particular values for s are 0 or 1. Inone embodiment, s is 0. In another embodiment, s is 1.

Each R⁸ is independently (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,(3-6C)cycloalkyl, cyano, nitro, halo,N,N-di(1-4C)alkylamino(2-4C)alkoxy, —OR^(8a), —C(O)OR^(8b), —SR^(8c),—S(O)R^(8d), —S(O)₂R^(8e) or —NR^(8f)R^(8g). Each R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f) and R^(8g) as used in R⁸ is independentlyhydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl or phenyl(1-4C)alkyl,where each phenyl group is unsubstituted or substituted by 1 or 2substituents independently selected from halo, (1-4C)alkyl and(1-4C)alkoxy. In addition, each alkyl and alkoxy group in R⁵ andR^(8a-8g) is optionally substituted with 1 to 5 fluoro substituents. Inone embodiment, each R⁸ independently represents halo, (1-3C)alkyl, or(1-3C)alkoxy, where the alkyl and alkoxy groups are optionallysubstituted with 1 to 3 fluoro substituents. In another embodiment, eachR⁸ is independently selected from fluoro, chloro, bromo, methyl,methoxy, trifluoromethyl or trifluoromethoxy. In a particularembodiment, R⁸ is —OR^(8a) where R^(8a) is hydrogen or methyl.

R⁹ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkyleneNR^(9a)R^(9b),and phenyl; or R⁹ may be taken together with R⁸ (and the carbon atom oratoms to which they are attached) to form a ring having 1 to 2 oxygenatoms, where the ring is unsubstituted or substituted by 1 or 2(1-4C)alkyl substituents. Each of R^(9a) and R^(9b) is independentlyhydrogen or (1-4C)alkyl. In addition, each alkyl group in R⁹ andR^(9a-9b) is optionally substituted with 1 to 5 fluoro substituents. Inone embodiment, R⁹ is hydrogen. In one embodiment, R⁹ is (1-4C)alkylsuch as methyl or methyl substituted with 2 or 3 fluoro substituents. Inanother embodiment, R⁹ is (1-4C)alkyleneNR^(9a)R^(9b), where each ofR^(9a) and R^(9b) is independently (1-4C)alkyl such as —(CH₂)₃N(CH₃)₂.In a particular embodiment, R⁹ is phenyl. In one embodiment, R⁹ is takentogether with R⁸ to form a ring having 1 to 2 oxygen atoms, and the ringis unsubstituted or substituted by 1 or 2 (1-4C)alkyl substituents.Exemplary R⁹/R⁸ chains include, —O(CH₂)—O—, —O—C(CH₃)₂—(CH₂)₂—,—O—(CH₂)₂—, and —O(CH₂)₂—O—.

The —OR⁹ group can be located at the ortho, meta or para position. Inone embodiment, the —OR⁹ group is located at the meta position; inanother embodiment, the —OR⁹ group is located at the ortho position; andin yet another embodiment, the —OR⁹ group is located at the paraposition.

In one particular embodiment of formulas I and Ic, Y is

The value for t is 0, 1, 2, or 3. Particular values for t are 1 or 2. Inone embodiment, t is 2.

The value for v is 0, 1, 2, 3, or 4. Particular values for v are 0, 1 or2. In one embodiment, v is 0.

Each R¹⁰ independently represents fluoro or (1-4C)alkyl, examples ofwhich include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl and tert-butyl. In addition, each alkyl and alkoxy group in R¹⁰is optionally substituted with 1 to 5 fluoro substituents. In oneembodiment, each R¹⁰ independently represents fluoro or (1-3C)alkyl, andin another embodiment, each R¹⁰ is independently selected from fluoro,methyl, ethyl or trifluoromethyl.

R¹¹ is selected from hydrogen, —OH, -(1-4C)alkyleneOH,—C(O)NR^(11a)R^(11b), and —CH₂C(O)NR^(11a)R^(11b). R^(11a) and R^(11b)are independently selected from hydrogen, (1-4C)alkyl, hydroxy,(1-4C)alkoxy, (1-4C)alkyleneOR^(11c), (3-6C)cycloalkyl, phenyloptionally substituted with hydroxy, and(1-4C)alkyleneC(O)NR^(11d)R^(11e). The (3-6C)cycloalkyl is unsubstitutedor substituted with 1 or 2 (1-6C)alkyl or —NR^(11d)R^(11e) groups. Eachof R^(11c), R^(11d) and R^(11e) is independently hydrogen or(1-4C)alkyl. In addition, each alkyl and alkoxy group in R¹¹ andR^(11a-e) is optionally substituted with 1 to 5 fluoro substituents. Inanother embodiment, R^(11a) is taken together with R^(11b) (and thenitrogen atom to which they are attached) to form a 3-7 membered ring,optionally substituted with hydroxyl. In one embodiment R¹¹ is selectedfrom hydrogen, —OH, and —C(O)NR^(11a)R^(11b), where R^(11a) and R^(11b)are hydrogen.

As noted in formula I, R¹¹ can be located at any carbon atom on thering. For example, when t is 2, R¹¹ can be located at the ortho, meta orpara position. In one embodiment, R¹¹ is located at the meta or paraposition; and in a particular embodiment, R¹¹ is located at the paraposition.

In yet another particular embodiment of formulas I and Ic, Y is—NR¹²R¹³. R¹² is selected from hydrogen, (1-4C)alkyl, -(1-4C)alkyleneOH,and -(1-4C)alkyleneheteroaryl. R¹³ is selected from (1-4C)alkyl,-(1-4C)alkyleneOH, -(1-4C)alkyleneheteroaryl, (3-6C)cycloalkyl,-(1-4C)alkylene(3-6C)cycloalkyl, and -(1-4C)alkyleneC(O)NR^(13a)R^(13b),where R^(13a) and R^(13b) are independently hydrogen or (1-4C)alkyl. Inone embodiment, R¹² is hydrogen. In another embodiment, R¹³ is(1-4C)alkyl, and in a particular embodiment, methyl or ethyl. In anotherembodiment, R¹³ is -(1-4C)alkyleneOH such as —CH₂CH₂OH. In yet anotherembodiment, R¹³ is (3-6C)cycloalkyl such as cyclopropyl or-(1-4C)alkylene(3-6C)cycloalkyl such as —CH₂-cyclopropyl. In anotherembodiment, R¹³ is -(1-4C)alkyleneC(O)NR^(13a)R^(13b) such as—CH₂C(O)NH₂. In another embodiment, R¹² is hydrogen and R¹³ is a-(1-4C)alkyleneheteroaryl group such as pyridin-4-ylmethyl,thiophen-2-ylmethyl, furan-2-ylmethyl and 1H-imidazol-2-ylmethyl. In yetanother embodiment, both R¹² and R¹³ are -(1-4C)alkyleneheteroarylgroups such as 1H-imidazol-2-ylmethyl.

Alternately, R¹² and R¹³ may be taken together (along with the nitrogenatom to which they are attached) to form a ring selected frompiperazinone, morpholine, and piperazine. When a piperazine ring isformed, the piperazine ring may be substituted with (R^(13c))_(w) wherew is 0 or an integer from 1 to 3. Each R^(13c) is independently selectedfrom (1-4C)alkyl, phenyl or benzyl, all of which may be optionallysubstituted with 1 to 5 fluoro substituents. In addition, two R^(13c)groups may be joined to form (1-3C)alkylene. In one embodiment, R¹² andR¹³ are taken together to form piperazin-2-one. In another embodiment,R¹² and R¹³ are taken together to form piperazine having a 1 carbonbridge such as a 2,5-diaza-bicyclo[2.2.1]heptane ring. In yet anotherembodiment, R¹² and R¹³ are taken together to form piperazine having a 1carbon bridge, and the piperazine ring is further substituted with(1-4C)alkyl such as methyl, phenyl or phenyl substituted with fluoro, orbenzyl.

A particular group of compounds of interest are compounds of formulas I,Ia-Ic, or Ia′ where a, b, and c are 0. In another group of compounds ofinterest, W represents O. Another group of compounds of interest arecompounds where m is 0. Other compounds of interest have Z¹ representedby —N(R⁴)C(O)—. Another group of compounds of interest are compounds ofwhere n is 0. In another group of compounds of interest, Ar¹ isphen-1,3-ylene or 2,5-thienylene. Another group of compounds of interestare compounds where q is 0. In another group of compounds of interest,Z² is —C(O)N(R⁶)—. Another group of compounds of interest are compoundswhere r is 0 or 1. Combinations of the foregoing are also of interest.For example, in one group of compounds of interest, a, b, c, m, n, q are0; W represents O; Z¹ is —N(R⁴)C(O)—; Ar¹ represents phen-1,3-ylene or2,5-thienylene; Z² is —C(O)N(R⁶)—; r is 1; and Y is

Another group of compounds of interest are compounds of formula I whereY is

where R⁷ is hydrogen; X¹ is selected from —CH₂— and —CH₂CH₂—; s is 0 ors is 1 and R⁸ is —OR^(8a) where R^(8a) is hydrogen or methyl; and R⁹ ishydrogen.

In another group of compounds of formula I and Ic of interest, Y is

where t is 1 or 2; v is 0; and R¹¹ is selected from hydrogen, —OH, and—C(O)NR^(11a)R^(11b), where R^(11a) and R^(11b) are hydrogen.

Another group of compounds of interest are compounds of formula I andIc, where Y is —NR¹²R¹³, where R¹² is hydrogen; R¹³ is selected frommethyl, ethyl, —CH₂CH₂OH, cyclopropyl, —CH₂-cyclopropyl, and—CH₂C(O)NH₂; or R¹² and R¹³ are taken together to form a piperazinonering.

In addition, particular compounds of formula I that are of interestinclude:

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxy-3-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-hydroxy-2-methoxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3-hydroxy-4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3,4-dihydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid1-{2-[methyl(3-{2-[(thiophen-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)amino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[(furan-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid 1-{2-[(3-{2-[(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[bis-(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({5-[2-(4-hydroxybenzylamino)ethylcarbamoyl]thiophene-2-carbonyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[methyl-(5-{2-[(pyridin-4-ylmethyl)amino]ethylcarbamoyl}thiophene-2-carbonyl)amino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-hydroxybenzylamino)propionylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{3-[2-(4-hydroxyphenyl)ethylamino]propionylamino}benzoylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[3-(4-hydroxybenzylamino)propionylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{3-[2-(4-hydroxyphenyl)ethylamino]propionylamino}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[2-(4-hydroxyphenyl)ethylamino]acetylamino}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{2-[2-(4-hydroxyphenyl)ethylamino]acetylamino}benzoylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxy-3-methoxybenzylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-hydroxybenzylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-hydroxy-3-methoxybenzylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(2-hydroxybenzylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(3-pyrrolidin-1-ylpropionylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(3-pyrrolidin-1-ylpropionylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[3-(4-carbamoylpiperidin-1-yl)propionylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-carbamoylpiperidin-1-yl)propionylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl[3-(2-pyrrolidin-1-yl-acetylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxypiperidin-1-yl)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-pyrrolidin-1-ylacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxypiperidin-1-yl)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-carbamoylpiperidin-1-yl)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(cyclopropylmethylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(cyclopropylmethylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{2-[(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{3-[(1H-imidazol-2-ylmethyl)amino]propionylamino}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{2-[(furan-2-ylmethyl)amino]ethylcarbamoyl}phenylcarbarnoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{3-[(furan-2-ylmethyl)amino]propionylamino}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[3-(3-cyclopropylaminopropionylamino)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(3-cyclopropylaminopropionylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(3-methylaminopropionylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(3-methylaminopropionylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxyethylamino)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(carbamoylmethylamino)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(methyl-{3-[2-(3-oxopiperazin-1-yl)acetylamino]benzoyl}amino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(cyclopropylmethylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(2-methylaminoacetylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[3-(2-ethylaminoacetylamino)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[3-(2-cyclopropylaminoacetylamino)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxyethylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(cyclopropylmethylamino)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(cyclopropylmethylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-methylaminoacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-ethylaminoacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid 1-{2-[3-(2-cyclopropylaminoacetylamino)benzoylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3-(2-methylaminoethylcarbamoyl)benzoyl]amino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxyethylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; and

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[2-(4-hydroxyphenyl)ethylamino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

or a pharmaceutically acceptable salt or solvate thereof.

Of particular interest are the following compounds having formula Ia:

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(4-hydroxy-3-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxy-2-methoxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3-hydroxy-4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3,4-dihydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({5-[2-(4-hydroxybenzylamino)ethylcarbamoyl]thiophene-2-carbonyl}methylamino)ethyl]piperidin-4-ylester; and

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[2-(4-hydroxyphenyl)ethylamino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

or a pharmaceutically acceptable salt or solvate thereof.

Of particular interest are the following compounds having formula Ib:

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-hydroxybenzylamino)propionylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{3-[2-(4-hydroxyphenyl)ethylamino]propionylamino}benzoylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[3-(4-hydroxybenzylamino)propionylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{3-[2-(4-hydroxyphenyl)ethylamino]propionylamino}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[2-(4-hydroxyphenyl)ethylamino]acetylamino}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{2-[2-(4-hydroxyphenyl)ethylamino]acetylamino}benzoylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxy-3-methoxybenzylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-hydroxybenzylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-hydroxy-3-methoxybenzylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester; and

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(2-hydroxybenzylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

or a pharmaceutically acceptable salt or solvate thereof.

Of particular interest are the following compounds having formula Ic:

biphenyl-2-ylcarbamic acid1-{2-[methyl(3-{2-[(thiophen-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)amino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[(furan-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[bis-(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[methyl-(5-{2-[(pyridin-4-ylmethyl)amino]ethylcarbamoyl}thiophene-2-carbonyl)amino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(3-pyrrolidin-1-ylpropionylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(3-pyrrolidin-1-ylpropionylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[3-(4-carbamoylpiperidin-1-yl)propionylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(4-carbamoylpiperidin-1-yl)propionylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl[3-(2-pyrrolidin-1-yl-acetylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxypiperidin-1-yl)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-pyrrolidin-1-ylacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxypiperidin-1-yl)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-carbamoylpiperidin-1-yl)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(cyclopropylmethylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[3-(cyclopropylmethylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{2-[(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{3-[(1H-imidazol-2-ylmethyl)amino]propionylamino}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{2-[(furan-2-ylmethyl)amino]ethylcarbamoyl}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(3-{3-[(furan-2-ylmethyl)amino]propionylamino}phenylcarbamoyl)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[3-(3-cyclopropylaminopropionylamino)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid 1-{2-[3-(3-cyclopropylaminopropionylamino)benzoylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(3-methylaminopropionylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(3-methylaminopropionylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxyethylamino)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(carbamoylmethylamino)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-(methyl-{3-[2-(3-oxopiperazin-1-yl)acetylamino]benzoyl}amino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(cyclopropylmethylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(2-methylaminoacetylamino)benzoyl]amino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[3-(2-ethylaminoacetylamino)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[3-(2-cyclopropylaminoacetylamino)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxyethylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{3-[2-(cyclopropylmethylamino)acetylamino]benzoylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(cyclopropylmethylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-methylaminoacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-ethylaminoacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-cyclopropylaminoacetylamino)benzoylamino]ethyl}piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{methyl-[3-(2-methylaminoethylcarbamoyl)benzoyl]amino}ethyl)piperidin-4-ylester; and

biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxyethylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester;

or a pharmaceutically acceptable salt or solvate thereof.

Particular compounds of formula Ia′ that are of interest include:

biphenyl-2-ylcarbamic acid1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[6-(2-aminoethylcarbamoyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[5-(2-aminoethylcarbamoyl)pyridine-3-carbonyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[6-(2-aminoethylcarbamoyl)pyridine-3-carbonyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[5-(2-aminoethylcarbamoyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[5-(2-aminoethylcarbamoyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-(2-{[4-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylester;

biphenyl-2-ylcarbamic acid1-{2-[3-(2-aminoethylcarbamoyl)benzoylamino]ethyl}piperidin-4-yl ester;and

biphenyl-2-ylcarbamic acid1-(2-{[5-(3-aminopropylcarbamoyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-ylester;

or a pharmaceutically acceptable salt or solvate thereof.

Definitions

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms. Representative alkyl groupsinclude, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like.

The term “alkylene” means a divalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 1 to 10 carbon atoms. Representativealkylene groups include, by way of example, methylene, ethane-1,2-diyl(“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl and the like.

The term “alkoxy” means a monovalent group of the formula (alkyl)-O—,where alkyl is as defined herein. Representative alkoxy groups include,by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,sec-butoxy, isobutoxy, tert-butoxy and the like.

The term “alkenyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon double bonds. Unless otherwisedefined, such alkenyl groups typically contain from 2 to 10 carbonatoms. Representative alkenyl groups include, by way of example,ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and thelike. The term “alkenylene” means a divalent alkenyl group.

The term “alkynyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwisedefined, such alkynyl groups typically contain from 2 to 10 carbonatoms. Representative alkynyl groups include, by way of example,ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. The term“alkynylene” means a divalent alkynyl group.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwisedefined, such aryl groups typically contain from 6 to 10 carbon ringatoms. Representative aryl groups include, by way of example, phenyl andnaphthalene-1-yl, naphthalene-2-yl, and the like. The term “arylene”means a divalent aryl group.

The term “azacycloalkyl” means a monovalent heterocyclic ring containingone nitrogen atom, i.e., a cycloalkyl group in which one carbon atom hasbeen replaced with a nitrogen atom. Unless otherwise defined, suchazacycloalkyl groups typically contain from 2 to 9 carbon atoms.Representative examples of an azacycloalkyl group are pyrrolidinyl andpiperidinyl groups. The term “azacycloalkylene” means a divalentazacycloakyl group. Representative examples of an azacycloalkylene groupare pyrrolidinylene and piperidinylene groups.

The term “cycloalkyl” means a monovalent saturated carbocyclichydrocarbon group. Unless otherwise defined, such cycloalkyl groupstypically contain from 3 to 10 carbon ring atoms. Representativecycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. The term “cycloalkylene” means adivalent cycloalkyl group.

The term “halo” means fluoro, chloro, bromo and iodo.

The term “heteroaryl” means a monovalent aromatic group having a singlering or two fused rings and containing in the ring at least oneheteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygenand sulfur. Unless otherwise defined, such heteroaryl groups typicallycontain from 5 to 10 total ring atoms. Representative heteroaryl groupsinclude, by way of example, monovalent species of pyrrole, imidazole,thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole,isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine,indole, benzofuran, benzothiophene, benzimidazole, benzthiazole,quinoline, isoquinoline, quinazoline, quinoxaline and the like, wherethe point of attachment is at any available carbon or nitrogen ringatom. The term “heteroarylene” means a divalent heteroaryl group.

The term “heterocyclyl” or “heterocyclic” means a monovalent saturatedor unsaturated (non-aromatic) group having a single ring or multiplecondensed rings and containing in the ring at least one heteroatom(typically 1 to 3 heteroatoms) selected from nitrogen, oxygen andsulfur. Unless otherwise defined, such heterocyclic groups typicallycontain from 2 to 9 total ring carbon atoms. Representative heterocyclicgroups include, by way of example, monovalent species of pyrrolidine,imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine,thiomorpholine, piperazine, 3-pyrroline and the like, where the point ofattachment is at any available carbon or nitrogen ring atom. The term“heterocyclene” means a divalent heterocyclyl or heterocyclic group.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown in parenthesespreceding the term. For example, the term “(1-4C)alkyl” means an alkylgroup having from 1 to 4 carbon atoms.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient such as a mammal (e.g., saltshaving acceptable mammalian safety for a given dosage regime). Suchsalts can be derived from pharmaceutically acceptable inorganic ororganic bases and from pharmaceutically acceptable inorganic or organicacids. Salts derived from pharmaceutically acceptable inorganic basesinclude ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, manganous, potassium, sodium, zinc and the like. Particularlypreferred are ammonium, calcium, magnesium, potassium and sodium salts.Salts derived from pharmaceutically acceptable organic bases includesalts of primary, secondary and tertiary amines, including substitutedamines, cyclic amines, naturally-occurring amines and the like such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. Salts derived frompharmaceutically acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic,malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic,naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, nicotinic,nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, p-toluenesulfonic, xinafoic and the like. Particularlypreferred are citric, hydrobromic, hydrochloric, isethionic, maleic,naphthalene-1,5-disulfonic, phosphoric, sulfuric and tartaric acids.

The term “salt thereof” means a compound formed when the hydrogen of anacid is replaced by a cation such as a metal cation or an organic cationand the like. Preferably, the salt is a pharmaceutically acceptablesalt. This is not required however, since some salts (e.g., salts ofintermediate compounds) are not intended to be administered to patients.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, i.e. a compound of formula I or apharmaceutically acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include, by way of example, water, methanol, ethanol,isopropanol, acetic acid and the like. When the solvent is water, thesolvate formed is a hydrate.

It will be appreciated that the term “or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof” is intended to include allpermutations of salts, solvates and stereoisomers such as a solvate of apharmaceutically acceptable salt of a stereoisomer of a compound offormula I.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.For example, a therapeutically effective amount for antagonizing amuscarinic receptor is that amount which will achieve the desiredantagonizing effect. Similarly, a therapeutically effective amount fortreating a pulmonary disorder is that amount that will achieve thedesired therapeutic result, which may be disease prevention,amelioration, suppression or alleviation, as described below.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as COPD) in a patientsuch as a mammal (particularly a human) that includes:

-   -   (a) preventing the disease or medical condition from occurring,        i.e., prophylactic treatment of a patient believed to be at risk        of contracting or being pre-disposed to such disease or medical        condition;    -   (b) ameliorating the disease or medical condition, i.e.,        eliminating or causing regression of the disease or medical        condition in a patient having such disease or medical condition;    -   (c) suppressing the disease or medical condition, i.e., slowing        or arresting the development of the disease or medical condition        in a patient having such disease or medical condition; or    -   (d) alleviating the symptoms of the disease or medical condition        in a patient having such disease or medical condition.

The term “unit dosage form” refers to a physically discrete unitsuitable for dosing a patient, i.e., each unit containing apredetermined quantity of a compound of the invention calculated toproduce the desired therapeutic effect either alone or in combinationwith one or more additional units. For example, such unit dosage formsmay be capsules, tablets, pills, and the like.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise undesirable. For example, the term“pharmaceutically acceptable carrier” refers to a material that can beincorporated into a composition and administered to a patient withoutcausing undesirable biological effects or interacting in a deleteriousmanner with other components of the composition. Such pharmaceuticallyacceptable materials typically have met the required standards oftoxicological and manufacturing testing, and include those materialsidentified as suitable inactive ingredients by the U.S. Food and Drugadministration.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitution reactionsuch as a nucleophilic substitution reaction. By way of example,representative leaving groups include chloro, bromo and iodo groups;sulfonic ester groups such as mesylate, tosylate, brosylate, nosylateand the like; and acyloxy groups such as acetoxy, trifluoroacetoxy andthe like.

The term “protected derivatives thereof” means a derivative of thespecified compound in which one or more functional groups of thecompound are protected from undesired reactions with a protecting orblocking group. Functional groups which may be protected include, by wayof example, carboxylic acid groups, amino groups, hydroxyl groups, thiolgroups, carbonyl groups and the like. Representative protecting groupsfor carboxylic acids include esters (such as a p-methoxybenzyl ester),amides and hydrazides; for amino groups, carbamates (such astert-butoxycarbonyl) and amides; for hydroxyl groups, ethers and esters;for thiol groups, thioethers and thioesters; for carbonyl groups,acetals and ketals; and the like. Such protecting groups are well-knownto those skilled in the art and are described, for example, in T. W.Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, ThirdEdition, Wiley, New York, 1999, and references cited therein.

The term “amino-protecting group” means a protecting group suitable forpreventing undesired reactions at an amino group. Representativeamino-protecting groups include, but are not limited to,tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS),tert-butyldimethylsilyl (TBS), and the like.

The term “carboxy-protecting group” means a protecting group suitablefor preventing undesired reactions at a carboxy group. Representativecarboxy-protecting groups include, but are not limited to, esters suchas methyl, ethyl, tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB),9-fluroenylmethyl (Fm), trimethylsilyl (TMS), tert-butyldimethylsilyl(TBS), diphenylmethyl (benzhydryl, DPM) and the like.

The term “hydroxyl-protecting group” means a protecting group suitablefor preventing undesirable reactions at a hydroxyl group. Representativehydroxyl-protecting groups include, but are not limited to, silyl groupsincluding tri(1-6C)alkylsilyl groups such as trimethylsilyl (TMS),triethylsilyl (TES), tert-butyldimethylsilyl (TBS) and the like; esters(acyl groups) including (1-6C)alkanoyl groups such as formyl, acetyl andthe like; arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB),9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and the like.Additionally, two hydroxyl groups can also be protected as an alkylidenegroup such as prop-2-ylidine, formed, for example, by reaction with aketone such as acetone.

General Synthetic Procedures

The biphenyl compounds of the invention can be prepared from readilyavailable starting materials using the following general methods, theprocedures set forth in the Examples, or by using other methods,reagents, and starting materials that are readily available to those ofordinary skill in the art. Although a particular embodiment of thepresent invention may be shown or described herein, those skilled in theart will recognize that all embodiments or aspects of the presentinvention can be readily prepared. It will also be appreciated thatwhere typical or preferred process conditions (i.e., reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. While the optimum reaction conditions may varydepending on the particular reactants or solvent used, such conditionscan be readily determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary or desired to preventcertain functional groups from undergoing undesired reactions. Thechoice of a suitable protecting group for a particular functional groupas well as suitable conditions for protection and deprotection of suchfunctional groups are well-known in the art. Protecting groups otherthan those illustrated in the procedures described herein may be used,if desired. For example, numerous protecting groups, and theirintroduction and removal, are described in T. W. Greene and G. M. Wuts,Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York,1999, and references cited therein.

By way of illustration, the compounds of the invention can be preparedby one or more of the following exemplary processes. Compounds offormulas I, Ia-c and Ia′ can be prepared by (a) reacting a compound offormula II:

or a salt thereof, with a compound of formula III:

wherein L¹ represents a leaving group.

Compounds of formulas I and Ib-c can also be prepared by (b) coupling acompound of formula IVa:

or a reactive derivative thereof, with a compound of formula Va:

or (b′) coupling a compound of formula IVb:

with a compound of formula Vb:

or a reactive derivative thereof. Compounds of formula Ia and Ia′ can beprepared by coupling a compound of formula IVb with a compound offormula Vb or a reactive derivative thereof.

Compounds of formulas I, Ia-c and Ia′ can also be prepared by (c)coupling a compound of formula VIa:

or a reactive derivative thereof, with a compound of formula VIIa:

Compounds of formulas I and Ib-c can also be prepared by (c′) coupling acompound of formula VIb:

with a compound of formula VIIb:

or a reactive derivative thereof.

Compounds of formulas I, Ia-c and Ia′ can be prepared by (d) reacting acompound of formula VIII:

wherein L² represents a leaving group, with a compound of formula IX:H—Y  IXwhere H—Y is:

depending upon which compound is being prepared, i.e., a compound offormula I, formula Ia, formula Ib or formula Ic. For preparing compoundof formula Ia′, H—Y is —NH₂ or a protected form thereof.

Compounds of formulas I, Ia-c and Ia′ can also be prepared by (e)reacting a compound of formula II with a compound of formula X:

in the presence of a reducing agent; or

Compounds of formulas I, Ia-c and Ia′ can also be prepared by (f)reacting a compound of formula XI:

with a compound of formula IX in the presence of a reducing agent.

Any of the aforementioned processes may also involve a step of (g)removing any protecting groups that may be present to provide a compoundof the invention (formulas I, Ia, Ib, Ic, or Ia′), and optionallyforming a pharmaceutically acceptable salt thereof.

Generally, if a salt of one of the starting materials is used in theprocesses described above, such as an acid addition salt, the salt istypically neutralized before or during the reaction process. Thisneutralization reaction is typically accomplished by contacting the saltwith one molar equivalent of a base for each molar equivalent of acidaddition salt.

The Z¹, Z² and Y substituents in the intermediates described in theabove processes, will vary depending upon whether compounds of formulaI, formula Ia, formula Ib, formula Ic, or formula Ia′ are beingprepared. For use in preparing compounds of formulas I, Ib, and Ic, theZ′ substituent in any intermediate will be —C(O)N(R⁴)— or —N(R⁴)C(O)—and Z² will be —C(O)N(R⁶)— or —N(R⁶)C(O)—. For preparing compounds offormula Ia or Ia′, the Z¹ substituent in any intermediate will be—N(R⁴)C(O)—, and the Z² substituent will be —C(O)N(R⁶)—. For use inpreparing compounds of formula I, the Y substituent in any intermediatewill be:

For use in preparing compounds of formula Ia, and Ib, the Y substituentin any intermediate will be:

For use in preparing compounds of formula Ic, the Y substituent in anyintermediate will be

For use in preparing compounds of formula Ia′, the Y substituent in anyintermediate will be —NH₂, or a protected form thereof.

In process (a), the reaction between the compounds of formula II andIII, the leaving represented by L¹ can be, for example, a halo groupsuch as chloro, bromo or iodo, or a sulfonic ester group such asmesylate or tosylate. The reaction is conveniently performed in thepresence of a base, for example, a tertiary amine such asdiisopropylethylamine. Convenient solvents include nitriles such asacetonitrile. The reaction is conveniently conducted at a temperature inthe range of from 0 to 100° C.

Compounds of formula II are generally known in the art, or can beprepared by deprotecting a compound of formula XII:

where P¹ represents an amino-protecting group such as a benzyl group.Benzyl groups are conveniently removed by reduction, using a hydrogen orammonium formate and a Group VIII metal catalyst such as palladium. WhenW represents NW^(a), the hydrogenation reaction is convenientlyperformed using Pearlman's catalyst (Pd(OH)₂).

Compounds of formula XII can be prepared by reacting an isocyanatecompound of formula XIII:

with a compound of formula XIV:

Compounds of formula III can be prepared starting from a correspondingcompound in which L¹ represents a hydroxyl group, for example, byreaction of a halogenating agent, such as thionyl chloride, to afford acompound of formula III in which L¹ represents halo such as chloro.Compounds in which L¹ represents a hydroxyl group may be prepared, forexample, by reacting a compound of formula Vb with an appropriateamino-substituted alcohol such as 2-aminoethanol or 3-aminopropan-1-ol.

In process (b), the term “reactive derivative” of compound IVa or Vb isintended to mean that the carboxylic acid is activated, for example, byforming an anhydride or carboxylic acid halide such as a carboxylic acidchloride. Alternatively, the carboxylic acid can be activated usingconventional carboxylic acid/amine coupling reagents, suchcarbodiimides, O-(7-azabenzotriazol-1-yl-N,N,N′,N′ tetramethyluroniumhexafluorophosphate (HATU) and the like. This reaction is convenientlyperformed under conventional amide bond-forming conditions. The processis conveniently conducted at a temperature in the range of from −10 to100° C.

Compounds of formula IVa can be prepared by reacting a compound offormula II with a compound of formula XV:L³-CH₂(CH₂)_(m)CH₂COOP²  XVwhere L³ represents a leaving group including, for example, a halo groupsuch as chloro, bromo or iodo, or a sulfonic ester group such asmesylate or tosylate; and P² represents a hydrogen atom or acarboxyl-protecting group such as a (1-4C)alkyl group. If necessary, thecarboxyl-protecting group P², is then removed, for example, byhydrolysis under conventional conditions such as by using lithiumhydroxide.

Compounds of formula Va can be prepared by reacting a compound offormula IX with a compound of formula XVI:

where P³ represents hydrogen or an amino-protecting group, such astert-butoxycarbonyl, and L⁴ represents a leaving group including, forexample, a halo group such as chloro, bromo or iodo, or a sulfonic estergroup such as mesylate or tosylate; followed if necessary, by removingan amino-protecting group P³. Alternatively, such compounds can beprepared by reductive amination of a compound of formula XVII:

using a compound of formula IX. The reducing agent may be, for example,hydrogen in the presence of a Group VIII metal catalyst such aspalladium, or a metal hydride reducing agent such as a borohydride,including sodium triacetoxyborohydride. Convenient solvents includealcohols such as methanol. The reaction is conveniently performed at atemperature in the range of from 0 to 100° C.

Compounds of formula IVb can be prepared by reacting a compound offormula II with a compound of formula XVIII:C(O)H(CH₂)_(m)CH₂NR⁴P⁴  XVIIIwhere P⁴ represents hydrogen or an amino-protecting group, such asbenzyl, in the presence of a reducing agent, such as sodiumtriacetoxyborohydride, followed if necessary by removing theamino-protecting group P⁴ by, for example, hydrogenation in the presenceof palladium.

Compounds of formula Vb can be prepared by reacting a compound offormula IX with a compound of formula XIX:

where P⁵ represents hydrogen or a carboxyl-protecting group such asmethyl or ethyl, and L⁵ represents a leaving group, followed ifnecessary by removing the carboxyl protecting group P⁵. Alternatively,such compounds can be prepared by reductive amination of a compound offormula XX with a compound of formula IX:

The reducing agent may be, for example, hydrogen in the presence of aGroup VIII metal catalyst such as palladium, or a metal hydride reducingagent such as a borohydride, including sodium triacetoxyborohydride.Convenient solvents include alcohols such as methanol. The reaction isconveniently performed at a temperature in the range of from 0 to 100°C.

Process (c) is conducted in a similar matter to that described inprocess (b), and the compounds of formula VIa, VIIa, VIb, and VII b areprepared in a similar manner as that described for the compounds offormula IVa, Va, Vb, Vb.

Referring to process (d), the leaving group represented by L² can be,for example, a halo group such as chloro, bromo or iodo, or a sulfonicester group such as mesylate or tosylate. This reaction is convenientlyperformed in the presence of a base, for example, a tertiary amine suchas diisopropylethylamine. Convenient solvents include nitrites such asacetonitrile. The reaction is conveniently conducted at a temperature inthe range of from 0 to 100° C. The compounds of formula VIII can beprepared by reacting a compound of formula VIa with a compound offormula XXI:

or by reacting a compound of formula VIb with a compound of formulaXXII:

The reaction is conveniently performed following, for example, themethod of process (b) described herein. Compounds of formula IX aregenerally known or can be prepared from readily available startingmaterials using well-known synthetic methods.

In process (e), the reducing agent may be, for example, hydrogen in thepresence of a Group VIII metal catalyst such as palladium, or a metalhydride reducing agent such as a borohydride, including sodiumtriacetoxyborohydride, optionally used in combination with a titaniumtetraalkoxide such as titanium tetraisopropoxide. Convenient solventsinclude alcohols such as methanol and halogenated hydrocarbons such asdichloromethane. The reaction is conveniently performed at a temperaturein the range of from 0 to 100° C.

The compound of formula X may be prepared by oxidizing a compoundcorresponding to formula III in which L¹ represents a hydroxyl group.Such oxidation reactions can be conducted, for example, using sulfurdioxide pyridine complex in dimethylsulfoxide in the presence of atertiary amine such as diisopropylethylamine.

In process (f), the reduction is preformed as described for process (e).

Compounds of formula XI may be prepared by reacting a compound offormula IVb with a compound of formula XXIII:

or a compound of formula VIb with a compound of formula XXIV:

in the presence of a carboxylic acid/amine coupling agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and1-hydroxybenzotriazole hydrate (HOBT) and the like.

As will be apparent to those skilled in the art, compounds of theinvention prepared by any of the aforementioned steps may be furtherderivatized to form other compounds of formula I using methods andreagents well-known in the art. By way of illustration, a compound offormula I may be reacted with bromine to afford a corresponding compoundof formula I in which R², for example, represents a bromo group.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth below.

Pharmaceutical Compositions and Formulations

The biphenyl compounds of the invention are typically administered to apatient in the form of a pharmaceutical composition or formulation. Suchpharmaceutical compositions may be administered to the patient by anyacceptable route of administration including, but not limited to,inhaled, oral, nasal, topical (including transdermal) and parenteralmodes of administration.

It will be understood that any form of the compounds of the invention,(i.e., free base, pharmaceutically acceptable salt, solvate, etc.) thatis suitable for the particular mode of administration can be used in thepharmaceutical compositions discussed herein.

Accordingly, one embodiment of the invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier or excipient and a therapeutically effective amount of acompound of formula I, or a pharmaceutically acceptable salt or solvateor stereoisomer thereof. The pharmaceutical composition may containother therapeutic and/or formulating agents if desired.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the invention or apharmaceutically acceptable salt or solvate or stereoisomer thereof, asthe active agent. Typically, such pharmaceutical compositions willcontain from about 0.01 to 95% by weight of the active agent; including,from about 0.01 to 30%, such as from about 0.01 to 10%.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable pharmaceutical composition for a particular mode ofadministration is well within the scope of those skilled in thepharmaceutical arts. Additionally, the ingredients for such compositionsare commercially available from, for example, Sigma, P.O. Box 14508, St.Louis, Mo. 63178. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials that can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols such aspropylene glycol; polyols such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; compressedpropellant gases such as chlorofluorocarbons and hydrofluorocarbons; andother non-toxic compatible substances employed in pharmaceuticalcompositions.

The pharmaceutical compositions of the invention are typically preparedby thoroughly and intimately mixing or blending a compound of theinvention with a pharmaceutically acceptable carrier and one or moreoptional ingredients. If necessary or desired, the resulting uniformlyblended mixture can then be shaped or loaded into tablets, capsules,pills, canisters, cartridges, dispensers and the like using conventionalprocedures and equipment.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for inhaled administration. Suitable pharmaceuticalcompositions for inhaled administration will typically be in the form ofan aerosol or a powder. Such compositions are generally administeredusing well-known delivery devices such as a nebulizer inhaler, ametered-dose inhaler (MDI), a dry powder inhaler (DPI) or a similardelivery device.

In a specific embodiment of the invention, the pharmaceuticalcomposition comprising the active agent is administered by inhalationusing a nebulizer inhaler. Such nebulizer devices typically produce astream of high velocity air that causes the pharmaceutical compositioncomprising the active agent to spray as a mist that is carried into thepatient's respiratory tract. Accordingly, when formulated for use in anebulizer inhaler, the active agent is typically dissolved in a suitablecarrier to form a solution. Alternatively, the active agent can bemicronized and combined with a suitable carrier to form a suspension ofmicronized particles of respirable size, where micronized is typicallydefined as having about 90% or more of the particles with a diameter ofless than about 10 μm. Suitable nebulizer devices are commerciallyavailable, for example, by PARI GmbH (Starnberg, German). Othernebulizer devices include Respimat (Boehringer Ingelheim) and thosedescribed, for example, in U.S. Pat. No. 6,123,068 to Lloyd et al. andWO 97/12687 (Eicher et al.), the disclosures of which are incorporatedherein by reference in their entirety.

A representative pharmaceutical composition for use in a nebulizerinhaler comprises an isotonic aqueous solution comprising from about0.05 μg/mL to about 10 mg/mL of a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof.

In another specific embodiment of the invention, the pharmaceuticalcomposition comprising the active agent is administered by inhalationusing a DPI. Such DPIs typically administer the active agent as afree-flowing powder that is dispersed in a patient's air-stream duringinspiration. In order to achieve a free flowing powder, the active agentis typically formulated with a suitable excipient such as lactose orstarch. Micronization is a common method of reducing crystal size tothat suitable for pulmonary delivery. Typically, the active agent ismicronized and combined with a suitable carrier to form a suspension ofmicronized particles of respirable size, where “micronized particles” or“micronized form” means at least about 90% of the particles have adiameter of less than about 10 μm. Other methods of reducing particlesize may also be used such as fine milling, chopping, crushing,grinding, milling, screening, trituration, pulverization, and so forth,as long as the desired particle size can be obtained.

A representative pharmaceutical composition for use in a DPI comprisesdry lactose having a particle size between about 1 μm and about 100 μmand micronized particles of a compound of formula I, or apharmaceutically acceptable salt or solvate or stereoisomer thereof.Such a dry powder formulation can be made, for example, by combining thelactose with the active agent and then dry blending the components.Alternatively, if desired, the active agent can be formulated without anexcipient. The pharmaceutical composition is then typically loaded intoa dry powder dispenser, or into inhalation cartridges or capsules foruse with a dry powder delivery device.

Examples of DPI delivery devices include Diskhaler (GlaxoSmithKline,Research Triangle Park, N.C.; see, e.g., U.S. Pat. No. 5,035,237 toNewell et al.); Diskus (GlaxoSmithKline; see, e.g., U.S. Pat. No.6,378,519 to Davies et al.); Turbuhaler (AstraZeneca, Wilmington, Del.;see, e.g., U.S. Pat. No. 4,524,769 to Wetterlin); Rotahaler(GlaxoSmithKline; see, e.g., U.S. Pat. No. 4,353,365 to Hallworth etal.) and Handihaler (Boehringer Ingelheim). Further examples of suitableDPI devices are described in U.S. Pat. No. 5,415,162 to Casper et al.,U.S. Pat. No. 5,239,993 to Evans, and U.S. Pat. No. 5,715,810 toArmstrong et al., and references cited therein. The disclosures of theaforementioned patents are incorporated herein by reference in theirentirety.

In yet another specific embodiment of the invention, the pharmaceuticalcomposition comprising the active agent is administered by inhalationusing an MDI, which typically discharges a measured amount of the activeagent or a pharmaceutically acceptable salt or solvate or stereoisomerthereof using compressed propellant gas. Accordingly, pharmaceuticalcompositions administered using an MDI typically comprise a solution orsuspension of the active agent in a liquefied propellant. Any suitableliquefied propellant may be employed including chlorofluorocarbons suchas CCl₃F, and hydrofluoroalkanes (HFAs) such as1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA 227). Due to concerns aboutchlorofluorocarbons affecting the ozone layer, formulations containingHFAs are generally preferred. Additional optional components of HFAformulations include co-solvents such as ethanol or pentane, andsurfactants such as sorbitan trioleate, oleic acid, lecithin, andglycerin. See, for example, U.S. Pat. No. 5,225,183 to Purewal et al.,EP 0717987 A2 (Minnesota Mining and Manufacturing Company), and WO92/22286 (Minnesota Mining and Manufacturing Company), the disclosuresof which are incorporated herein by reference in their entirety.

A representative pharmaceutical composition for use in a metered-doseinhaler comprises from about 0.01 to 5% by weight of a compound offormula I, or a pharmaceutically acceptable salt or solvate orstereoisomer thereof; from about 0 to 20% by weight ethanol; and fromabout 0 to 5% by weight surfactant; with the remainder being an HFApropellant.

Such compositions are typically prepared by adding chilled orpressurized hydrofluoroalkane to a suitable container containing theactive agent, ethanol (if present) and the surfactant (if present). Toprepare a suspension, the active agent is micronized and then combinedwith the propellant. The formulation is then loaded into an aerosolcanister, which forms a portion of a metered-dose inhaler device.Examples of metered-dose inhaler devices developed specifically for usewith HFA propellants are described in U.S. Pat. Nos. 6,006,745 toMarecki and 6,143,277 to Ashurst et al. Alternatively, a suspensionformulation can be prepared by spray drying a coating of surfactant onmicronized particles of the active agent. See, for example, WO 99/53901(Glaxo Group Ltd.) and WO 00/61108 (Glaxo Group Ltd.). The disclosuresof the aforementioned patents and publications are incorporated hereinby reference in their entirety.

For additional examples of processes of preparing respirable particles,and formulations and devices suitable for inhalation dosing see U.S.Pat. No. 6,268,533 to Gao et al., U.S. Pat. No. 5,983,956 to Trofast;U.S. Pat. No. 5,874,063 to Briggner et al.; and U.S. Pat. No. 6,221,398to Jakupovic et al.; and WO 99/55319 (Glaxo Group Ltd.) and WO 00/30614(AstraZeneca AB); the disclosures of which are incorporated herein byreference in their entirety.

In another embodiment, the pharmaceutical compositions of the inventionare suitable for oral administration. Suitable pharmaceuticalcompositions for oral administration may be in the form of capsules,tablets, pills, lozenges, cachets, dragees, powders, granules; or as asolution or a suspension in an aqueous or non-aqueous liquid; or as anoil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup;and the like; each containing a predetermined amount of a compound ofthe invention as an active ingredient. The pharmaceutical compositionmay be packaged in a unit dosage form.

When intended for oral administration in a solid dosage form (i.e., ascapsules, tablets, pills and the like), the pharmaceutical compositionsof the invention will typically comprise a compound of the presentinvention as the active ingredient and one or more pharmaceuticallyacceptable carriers such as sodium citrate or dicalcium phosphate.Optionally or alternatively, such solid dosage forms may also comprise:fillers or extenders such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; binders such as carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia;humectants such as glycerol; disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and/or sodium carbonate; solution retarding agents such asparaffin; absorption accelerators such as quaternary ammonium compounds;wetting agents such as cetyl alcohol and/or glycerol monostearate;absorbents such as kaolin and/or bentonite clay; lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and/or mixtures thereof; coloring agents; andbuffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the pharmaceutical compositions of the invention. Examples ofpharmaceutically acceptable antioxidants include: water-solubleantioxidants such as ascorbic acid, cysteine hydrochloride, sodiumbisulfate, sodium metabisulfate sodium sulfite and the like; oil-solubleantioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA),butylated hydroxytoluene (BHT), lecithin, propyl gallate,alpha-tocopherol, and the like; and metal-chelating agents such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like. Coating agents for tablets,capsules, pills and like, include those used for enteric coatings suchas cellulose acetate phthalate (CAP), polyvinyl acetate phthalate(PVAP), hydroxypropyl methylcellulose phthalate, methacrylicacid-methacrylic acid ester copolymers, cellulose acetate trimellitate(CAT), carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and the like.

If desired, the pharmaceutical compositions of the invention may also beformulated to provide slow or controlled release of the activeingredient using, by way of example, hydroxypropyl methyl cellulose invarying proportions; or other polymer matrices, liposomes and/ormicrospheres.

In addition, the pharmaceutical compositions of the invention mayoptionally contain opacifying agents and may be formulated so that theyrelease the active ingredient only, or preferentially, in a certainportion of the gastrointestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Such liquid dosage formstypically comprise the active ingredient and an inert diluent such as,for example, water or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (e.g., cottonseed, groundnut, corn, germ,olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Suspensions, in addition to the active ingredient, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example, acompound of the invention can be admixed with permeation enhancers suchas propylene glycol, polyethylene glycol monolaurate,azacycloalkan-2-ones and the like, and incorporated into a patch orsimilar delivery system. Additional excipients including gelling agents,emulsifiers and buffers, may be used in such transdermal compositions ifdesired.

The compounds of the invention can also be co-administered with othertherapeutic agents. This combination therapy involves using a compoundof the invention combined with one or more of these secondary agents,either formulated together (e.g., packaged together in a singleformulation) or formulated separately (e.g., packaged as separate unitdosage forms). Methods of formulating multiple agents together in thesame formulation or in separate unit dosage forms, are well known in theart.

The additional therapeutic agent(s) can be selected from otherbronchodilators (e.g., PDE₃ inhibitors, adenosine 2b modulators and β₂adrenergic receptor agonists); anti-inflammatory agents (e.g., steroidalanti-inflammatory agents such as corticosteroids; non-steroidalanti-inflammatory agents (NSAIDs), and PDE₄ inhibitors); othermuscarinic receptor antagonists (i.e., antichlolinergic agents);antiinfective agents (e.g., Gram positive and Gram negative antibioticsor antivirals); antihistamines; protease inhibitors; and afferentblockers (e.g., D₂ agonists and neurokinin modulators).

One particular embodiment of the invention is directed to a compositioncomprising (a) a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof; and(b) a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of an agent selected from a steroidal anti-inflammatoryagent such as a corticosteroid; a β₂ adrenergic receptor agonist; aphosphodiesterase-4 inhibitor; or a combination thereof; wherein thecompound of formula I and the agent are formulated together orseparately. In another embodiment, (b) is a pharmaceutically acceptablecarrier and a therapeutically effective amount of a β₂ adrenergicreceptor agonist and a steroidal anti-inflammatory agent. The secondaryagents can be used in the form of pharmaceutically acceptable salts orsolvates, and if appropriate, as optically pure stereoisomers.

Representative β₂ adrenergic receptor agonists that can be used incombination with compounds of the invention include, but are not limitedto, salmeterol, salbutamol, formoterol, salmefamol, fenoterol,terbutaline, albuterol, isoetharine, metaproterenol, bitolterol,pirbuterol, levalbuterol and the like, or pharmaceutically acceptablesalts thereof. Other β₂ adrenergic receptor agonists that can be usedinclude, but are not limited to,3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideand3-(-3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamideand related compounds described in WO 02/066422 (Glaxo Group Ltd.);3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-phenyl]imidazolidine-2,4-dioneand related compounds described in WO 02/070490 (Glaxo Group Ltd.);3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzenesulfonamide,3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzenesulfonamide,3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzenesulfonamide,N-(tert-butyl)-3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]-oxy}butyl)benzenesulfonamide,N-(tert-butyl)-3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)-hexyl]oxy}butyl)-benzenesulfonamide,N-(tert-butyl)-3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]-oxy}butyl)benzenesulfonamideand related compounds described in WO 02/076933 (Glaxo Group Ltd.);4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenoland related compounds described in WO 03/024439 (Glaxo Group Ltd.);N-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamineand related compounds described in U.S. Pat. No. 6,576,793 to Moran etal.;N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamineand related compounds described in U.S. Pat. No. 6,653,323 to Moran etal.; and pharmaceutically acceptable salts thereof. In a particularembodiment, the β₂-adrenoreceptor agonist is a crystallinemonohydrochloride salt ofN-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine. When employed, the β₂-adrenoreceptor agonist will be presentin the pharmaceutical composition in a therapeutically effective amount.Typically, the β₂-adrenoreceptor agonist will be present in an amountsufficient to provide from about 0.05 μg to 500 μg per dose. Thedisclosures of the aforementioned patents and publications areincorporated herein by reference in their entirety.

Representative steroidal anti-inflammatory agents that can be used incombination with compounds of the invention include, but are not limitedto, methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydrofuran-3S-yl) ester, beclomethasone esters (e.g.,the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g., the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,ST-126 and the like, or pharmaceutically-acceptable salts thereof. Whenemployed, the steroidal anti-inflammatory agent will be present in thecomposition in a therapeutically effective amount. Typically, thesteroidal anti-inflammatory agent will be present in an amountsufficient to provide from about 0.05 μg to 500 μg per dose.

An exemplary combination is a compound of formula I, or pharmaceuticallyacceptable salt or solvate or stereoisomer thereof, co-administered withsalmeterol as the β₂ adrenergic receptor agonist, and fluticasonepropionate as the steroidal anti-inflammatory agent. Another exemplarycombination is a compound of formula I, or pharmaceutically acceptablesalt or solvate or stereoisomer thereof, co-administered with acrystalline monohydrochloride salt ofN-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamineas the β₂-adrenoreceptor agonist, and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester as the steroidal anti-inflammatory agent. Asnoted above, these agents can be formulated together or separately.

Other suitable combinations include, for example, otheranti-inflammatory agents, e.g., NSAIDs (e.g., sodium cromoglycate,nedocromil sodium, and phosphodiesterase (PDE) inhibitors such astheophylline, PDE4 inhibitors and mixed PDE3/PDE4 inhibitors);leukotriene antagonists (e.g., monteleukast); inhibitors of leukotrienesynthesis; iNOS inhibitors; protease inhibitors such as tryptase andelastase inhibitors; beta-2 integrin antagonists and adenosine receptoragonists or antagonists (e.g., adenosine 2a agonists); cytokineantagonists (e.g., chemokine antagonists such as, an interleukinantibody (αIL antibody), specifically, an αIL-4 therapy, an αIL-13therapy, or a combination thereof); or inhibitors of cytokine synthesis.

Representative phosphodiesterase-4 (PDE4) inhibitors or mixed PDE3/PDE4inhibitors that can be used in combination with the compounds of theinvention include, but are not limited to cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid and the like, or pharmaceutically acceptable salts thereof. Otherrepresentative PDE4 or mixed PDE4/PDE3 inhibitors include AWD-12-281(elbion); NCS-613 (INSERM); D-4418 (Chiroscience and Schering-Plough);CI-1018 or PD-168787 (Pfizer); benzodioxole compounds described inWO99/16766 (Kyowa Hakko); K-34 (Kyowa Hakko); V-11294A (Napp);roflumilast (Byk-Gulden); pthalazinone compounds described in WO99/47505(Byk-Gulden); Pumafentrine (Byk-Gulden, now Altana); arofylline(Almirall-Prodesfarma); VM554/UM565 (Vernalis); T-440 (Tanabe Seiyaku);and T2585 (Tanabe Seiyaku).

Representative muscarinic antagonists (i.e., anticholinergic agents)that can be used in combination with the compounds of the inventioninclude, but are not limited to, atropine, atropine sulfate, atropineoxide, methylatropine nitrate, homatropine hydrobromide, hyoscyamine (d,l) hydrobromide, scopolamine hydrobromide, ipratropium bromide,oxitropium bromide, tiotropium bromide, methantheline, propanthelinebromide, anisotropine methyl bromide, clidinium bromide, copyrrolate(Robinul), isopropamide iodide, mepenzolate bromide, tridihexethylchloride (Pathilone), hexocyclium methylsulfate, cyclopentolatehydrochloride, tropicamide, trihexyphenidyl hydrochloride, pirenzepine,telenzepine, AF-DX 116 and methoctramine and the like, or apharmaceutically acceptable salt thereof; or, for those compounds listedas a salt, alternate pharmaceutically acceptable salt thereof.

Representative antihistamines (i.e., H₁-receptor antagonists) that canbe used in combination with the compounds of the invention include, butare not limited to, ethanolamines such as carbinoxamine maleate,clemastine fumarate, diphenylhydramine hydrochloride and dimenhydrinate;ethylenediamines such as pyrilamine amleate, tripelennaminehydrochloride and tripelennamine citrate; alkylamines such aschlorpheniramine and acrivastine; piperazines such as hydroxyzinehydrochloride, hydroxyzine pamoate, cyclizine hydrochloride, cyclizinelactate, meclizine hydrochloride and cetirizine hydrochloride;piperidines such as astemizole, levocabastine hydrochloride, loratadineor its descarboethoxy analogue, terfenadine and fexofenadinehydrochloride; azelastine hydrochloride; and the like, or apharmaceutically acceptable salt thereof; or, for those compounds listedas a salt, alternate pharmaceutically acceptable salt thereof.

Unless otherwise indicated, exemplary suitable doses for the othertherapeutic agents administered in combination with a compound of theinvention are in the range of about 0.05 μg/day to 100 mg/day.

The following formulations illustrate representative pharmaceuticalcompositions of the invention, as well as exemplary methods ofpreparation. One or more secondary agents can optionally be formulatedwith the compound of the invention (primary active agent). Alternately,the secondary agents(s) can be formulated separately and co-administeredwith the primary active agent, either simultaneously or sequentially.For example, in one embodiment, a single dry powder formulation can bemanufactured to include both the compound of the invention and one ormore secondary agents. In another embodiment, one formulation ismanufactured to contain the compound of the invention and separateformulation(s) are manufactured to contain the secondary agent(s). Suchdry powder formulations can then be packaged in separate blister packsand administered with a single DPI device.

Exemplary Dry Powder Formulation for Administration by Inhalation

0.2 mg of a compound of the invention is micronized and then blendedwith 25 mg of lactose. The blended mixture is then loaded into a gelatininhalation cartridge. The contents of the cartridge are administeredusing a powder inhaler.

Exemplary Dry Powder Formulation for Administration by a Dry PowderInhaler

A dry powder is prepared having a bulk formulation ratio of micronizedcompound of the invention (active agent) to lactose of 1:200. The powderis packed into a dry powder inhalation device capable of deliveringbetween about 10 μg and 100 μg of active agent per dose.

Exemplary Formulations for Administration by a Metered Dose Inhaler

A suspension containing 5 wt % of a compound of the invention (activeagent) and 0.1 wt % lecithin is prepared by dispersing 10 g of theactive agent as micronized particles with a mean size less than 10 μm ina solution formed from 0.2 g of lecithin dissolved in 200 mL ofdemineralized water. The suspension is spray dried and the resultingmaterial is micronized to particles having a mean diameter less than 1.5μm. The particles are loaded into cartridges with pressurized1,1,1,2-tetrafluoroethane.

Alternately, a suspension containing 5 wt % of the active agent, 0.5 wt% lecithin, and 0.5 wt % trehalose is prepared by dispersing 5 g of theactive agent as micronized particles with a mean size less than 10 μm ina colloidal solution formed from 0.5 g of trehalose and 0.5 g oflecithin dissolved in 100 mL of demineralized water. The suspension isspray dried and the resulting material is micronized to particles havinga mean diameter less than 1.5 μm. The particles are loaded intocanisters with pressurized 1,1,1,2-tetrafluoroethane.

Exemplary Aqueous Aerosol Formulation for Administration by Nebulizer

A pharmaceutical composition is prepared by dissolving 0.5 mg of acompound of the invention (active agent) in 1 mL of a 0.9% sodiumchloride solution acidified with citric acid. The mixture is stirred andsonicated until the active agent is dissolved. The pH of the solution isadjusted to a value in the range of from 3 to 8 (typically about 5) bythe slow addition of NaOH.

Exemplary Hard Gelatin Capsule Formulation for Oral Administration

The following ingredients are thoroughly blended and then loaded into ahard gelatin capsule: 250 mg of a compound of the invention, 200 mg oflactose (spray-dried), and 10 mg of magnesium stearate, for a total of460 mg of composition per capsule.

Exemplary Suspension Formulation for Oral Administration

The following ingredients are mixed to form a suspension containing 100mg of active ingredient per 10 mL of suspension.

Ingredients Amount Compound of the invention 1.0 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilledwater q.s. to 100 mL

Exemplary Injectable Formulation

The following ingredients are blended and the pH is adjusted to 4±0.5using 0.5 N HCl or 0.5 N NaOH.

Ingredients Amount Compound of the invention 0.2 g Sodium acetate buffersolution (0.4 M) 2.0 mL HCl (0.5 N) or NaOH (0.5 N) q.s. to pH 4 Water(distilled, sterile) q.s. to 20 mL

Utility

The biphenyl compounds of the invention are expected to be useful asmuscarinic receptor antagonists and therefore, such compounds areexpected to be useful for treating medical conditions mediated bymuscarinic receptors, i.e., medical conditions which are ameliorated bytreatment with a muscarinic receptor antagonist. Such medical conditionsinclude, by way of example, pulmonary disorders or diseases includingthose associated with reversible airway obstruction such as chronicobstructive pulmonary disease (e.g., chronic and wheezy bronchitis andemphysema), asthma, pulmonary fibrosis, allergic rhinitis, rhinorrhea,and the like. Other medical conditions that can be treated withmuscarinic receptor antagonists are genitourinary tract disorders suchas overactive bladder or detrusor hyperactivity and their symptoms;gastrointestinal tract disorders such as irritable bowel syndrome,diverticular disease, achalasia, gastrointestinal hypermotilitydisorders and diarrhea; cardiac arrhythmias such as sinus bradycardia;Parkinson's disease; cognitive disorders such as Alzheimer's disease;dismenorrhea; and the like.

In one embodiment, compounds of the invention are useful for treatingsmooth muscle disorders in mammals, including humans and their companionanimals (e.g., dogs, cats etc.). Such smooth muscle disorders include,by way of illustration, overactive bladder, chronic obstructivepulmonary disease and irritable bowel syndrome.

When used to treat smooth muscle disorders or other conditions mediatedby muscarinic receptors, compounds of the invention will typically beadministered orally, rectally, parenterally or by inhalation in a singledaily dose or in multiple doses per day. The amount of active agentadministered per dose or the total amount administered per day willtypically be determined by the patient's physician and will depend onsuch factors as the nature and severity of the patients condition, thecondition being treated, the age and general health of the patient, thetolerance of the patient to the active agent, the route ofadministration and the like.

Typically, suitable doses for treating smooth muscle disorders or otherdisorders mediated by muscarinic receptors will range from about 0.14μg/kg/day to 7 mg/kg/day of active agent; including from about 0.15μg/kg/day to 5 mg/kg/day. For an average 70 kg human, this would amountto about 10 μg to 500 mg per day of active agent.

In a specific embodiment, the compounds of the invention are useful fortreating pulmonary or respiratory disorders, such as COPD or asthma, inmammals including humans. When used to treat such disorders, thecompounds of the invention will typically be administered by inhalationin multiple doses per day, in a single daily dose or a single weeklydose. Generally, the dose for treating a pulmonary disorder will rangefrom about 10 μg/day to 200 μg/day. As used herein, COPD includeschronic obstructive bronchitis and emphysema (see, for example, Barnes,Chronic Obstructive Pulmonary Disease, N Engl J Med 343:269-78 (2000)).

When used to treat a pulmonary disorder, compounds of the invention areoptionally administered in combination with other therapeutic agentssuch as a β₂-adrenoreceptor agonist; a corticosteroid, a non-steroidalanti-inflammatory agent, or combinations thereof.

When administered by inhalation, compounds of the invention typicallyhave the effect of producing bronchodilation. Accordingly, oneembodiment of the invention is directed to a method of producingbronchodilation in a patient, comprising administering to a patient abronchodilation-producing amount of a compound of the invention.Generally, the therapeutically effective dose for producingbronchodilation will range from about 10 μg/day to 200 μg/day.

In another embodiment, compounds of the invention are used to treatoveractive bladder. When used to treat overactive bladder, the compoundsof the invention will typically be administered orally in a single dailydose or in multiple doses per day; preferably in a single daily dose. Inone embodiment, the dose for treating overactive bladder will range fromabout 1.0 to 500 mg/day.

In yet another embodiment, compounds of the invention are used to treatirritable bowel syndrome. When used to treat irritable bowel syndrome,the compounds of the invention will typically be administered orally orrectally in a single daily dose or in multiple doses per day. In oneembodiment, the dose for treating irritable bowel syndrome will rangefrom about 1.0 to 500 mg/day.

Since compounds of the invention are muscarinic receptor antagonists,such compounds are also useful as research tools for investigating orstudying biological systems or samples having muscarinic receptors. Suchbiological systems or samples may comprise M₁, M₂, M₃, M₄ and/or M₅muscarinic receptors. Any suitable biological system or sample havingmuscarinic receptors may be employed in such studies, which may beconducted either in vitro or in vivo. Representative biological systemsor samples suitable for such studies include, but are not limited to,cells, cellular extracts, plasma membranes, tissue samples, mammals(such as mice, rats, guinea pigs, rabbits, dogs, pigs, etc.), and thelike.

In this embodiment, a biological system or sample comprising amuscarinic receptor is contacted with a muscarinic receptor-antagonizingamount of a compound of the invention. The effects of antagonizing themuscarinic receptor are then determined using conventional proceduresand equipment such as radioligand binding assays and functional assays.Such functional assays include ligand-mediated changes in intracellularcyclic adenosine monophosphate (cAMP), ligand-mediated changes inactivity of the enzyme adenylyl cyclase (which synthesizes cAMP),ligand-mediated changes in incorporation of guanosine5′-O-(γ-thio)triphosphate ([³⁵S]GTPγS) into isolated membranes viareceptor catalyzed exchange of [³⁵S]GTPγS for guanosine 5′-diphosphate(GDP), ligand-mediated changes in free intracellular calcium ions(measured, for example, with a fluorescence-linked imaging plate readeror FLIPR® from Molecular Devices, Inc.). Compounds of the invention willantagonize or decrease the activation of muscarinic receptors in any ofthe functional assays listed above, or assays of a similar nature. Amuscarinic receptor-antagonizing amount of a compound of the inventionwill typically range from about 0.1 to 100 nanomolar.

Additionally, compounds of the invention can be used as research toolsfor discovering new compounds that have muscarinic receptor antagonistactivity. In this embodiment, muscarinic receptor binding data (e.g., asdetermined by in vitro radioligand displacement assays) for a testcompound or a group of test compounds is compared to the muscarinicreceptor binding data for a compound of the invention to identify thosetest compounds that have about equal or superior muscarinic receptorbinding, if any. This aspect of the invention includes, as separateembodiments, both the generation of comparison data (using theappropriate assays) and the analysis of the test data to identify testcompounds of interest.

In another embodiment, compounds of the invention are used to antagonizea muscarinic receptor in a biological system, and a mammal in particularsuch as mice, rats, guinea pigs, rabbits, dogs, pigs, humans and soforth. In this embodiment, a therapeutically effective amount of acompound of formula I is administered to the mammal. The effects ofantagonizing the muscarinic receptor can then determined usingconventional procedures and equipment, examples of which are describedabove.

Among other properties, compounds of the invention have been found to bepotent inhibitors of M₃ muscarinic receptor activity. Accordingly, in aspecific embodiment, the invention is directed to compounds of formula Ihaving an inhibition dissociation constant (K_(i)) for the M₃ receptorsubtype of less than or equal to 10 nM, as determined, for example, byan in vitro radioligand displacement assay. In one embodiment, compoundsof the invention have a K_(i) value for the M₃ receptor subtype of lessthan or equal to 5 nM.

Additionally, compounds of the invention are expected to possess adesirable duration of action. Accordingly, in another specificembodiment, the invention is directed to compounds of formula I having aduration of action greater than or equal to about 24 hours. Moreover,compounds of the invention are also expected to possess reduced sideeffects, such as dry mouth, at efficacious doses when administered byinhalation compared to other known muscarinic receptor antagonistsadministered by inhalation (such as tiotropium).

These and other properties, as well as the utility of the compounds, canbe demonstrated using various in vitro and in vivo assays that arewell-known to those skilled in the art. For example, representativeassays are described in further detail in the following Examples.

EXAMPLES

The Preparations and Examples illustrate specific embodiments of theinvention. The following abbreviations have the following meaningsunless otherwise indicated and any other abbreviations used herein andnot defined have their standard meaning:

AC adenylyl cyclase ACh acetylcholine ACN acetonitrile BSA bovine serumalbumin cAMP 3′-5′ cyclic adenosine monophosphate CHO Chinese hamsterovary cM₅ cloned chimpanzee M₅ receptor DCM dichloromethane (i.e.,methylene chloride) DIPEA N,N-diisopropylethylamine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dPBS Dulbecco's phosphatebuffered saline EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride EDTA ethylenediaminetetraacetic acid EtOAc ethyl acetateEtOH ethanol FBS fetal bovine serum FLIPR fluorometric imaging platereader HATU O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HBSS Hank's buffered salt solution HEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid hM₁ cloned human M₁receptor hM₂ cloned human M₂ receptor hM₃ cloned human M₃ receptor hM₄cloned human M₄ receptor hM₅ cloned human M₅ receptor HOAc acetic acidHOBT 1-hydroxybenzotriazole hydrate HPLC high-performance liquidchromatography IPA isopropanol LCMS liquid chromatography massspectrometry MCh methylcholine MeOH methanol MTBE methyl t-butyl etherNa(OAc)₃BH sodium triacetoxyborohydride TFA trifluoroacetic acid THFtetrahydrofuran

Any other abbreviations used herein but not defined have their standard,generally accepted meaning. Unless noted otherwise, all materials, suchas reagents, starting materials and solvents, were purchased fromcommercial suppliers (such as Sigma-Aldrich, Fluka, and the like) andwere used without further purification.

Unless otherwise indicated, HPLC analysis was conducted using an Agilent(Palo Alto, Calif.) Series 1100 instrument equipped with Zorbax Bonus RP2.1×50 mm columns (Agilent) having a 3.5 micron particle size. Detectionwas by UV absorbance at 214 nm. The mobile phases employed were asfollows (by volume): A is ACN (2%), water (98%) and TFA (0.1%); and B isACN (90%), water (10%) and TFA (0.1%). HPLC 10-70 data was obtainedusing a flow rate of 0.5 ml/minute of 10 to 70% B over a 6 minutegradient (with the remainder being A). Similarly, HPLC 5-35 data andHPLC 10-90 data were obtained using 5 to 35% B; or 10 to 90% B over a 5minute gradient.

LCMS data were obtained with an Applied Biosystems (Foster City, Calif.)Model API-150EX instrument. LCMS 10-90 data was obtained using 10 to 90%Mobile Phase B over a 5 minute gradient.

Small-scale purification was conducted using an API-150EX PrepWorkstation system from Applied Biosystems. The mobile phases employedwere as follows (by volume): A is water and 0.05% TFA; and B is ACN and0.05% TFA. For arrays (typically about 3 to 50 mg recovered sample size)the following conditions were used: 20 mL/min flow rate; 15 minutegradients and a 20 mm×50 mm Prism RP column with 5 micron particles(Thermo Hypersil-Keystone, Bellefonte, Pa.). For larger scalepurifications (typically greater than 100 mg crude sample), thefollowing conditions were used: 60 mL/min flow rate; 30 minute gradientsand a 41.4 mm×250 mm Microsorb BDS column with 10 micron particles(Varian, Palo Alto, Calif.).

Preparation 1 N-(2-tert-Butoxycarbonylaminoethyl)isophthalamic AcidMethyl Ester

Mono-methyl isophthalate (10.0 g, 55.5 mmol), t-butyl n-(2-aminoethyl)carbamate (8.89 g, 55.5 mmol, 1.0 eq) and EDCI (12.2 g, 63.8 mmol, 1.15eq) were dissolved in 270 mL DCM, followed by the addition of DIPEA(29.0 mL, 166 mmol, 3.0 eq). The reaction was allowed to stir at roomtemperature overnight. It was then taken up in 100 mL of DCM, washedwith a 1:1 solution of 1.0 N HCl in brine, water, and a 1:1 solution ofbrine in saturated NaHCO₃. The organic layer was dried over Na₂SO₄,filtered and concentrated to afford the product as a light yellow solid(12.81 g, 72%).

Preparation 2 N-(2-tert-Butoxycarbonylaminoethyl)isophthalamic Acid

38.8 g of N-(2-tert-butoxycarbonylaminoethyl)isophthalamic acid methylester (prepared as described in Preparation 1) was dissolved in asolution of THF/DMF (1:1, 740 mL), and NaOH (111 mL of 10 N solution,1.11 mol, 10.0 eq) was added. The reaction was stirred at roomtemperature overnight. The pH was then adjusted to pH 9 using 1.0 N HCland concentrated to ˜250 mL volume under vacuum. The mixture wasfiltered to remove impurities. The filtrate was further acidified to pH5 by slow addition of 1.0 N HCl, and concentrated to ˜200 mL volume. Theprecipitate was collected by filtration, rinsed with water and EtOAc,and dried under vacuum to give the product as a white solid (17.75 g,52%).

For large scale synthesis, the reaction was carried out in MTBE using 2NNaOH (3 eq). The title compound was further purified via crystallizationin MeOH.

Preparation 3 Biphenyl-2-ylcarbamic Acid Piperidin-4-yl Ester

Biphenyl-2-isocyanate (97.5 g, 521 mmol) and4-hydroxy-N-benzylpiperidine (105 g, 549 mmol) were heated together at70° C. for 12 hours. The reaction mixture was then cooled to 50° C.,EtOH (1 L) was added and then 6M HCl (191 mL) was added slowly. Theresulting mixture was then cooled to ambient temperature, ammoniumformate (98.5 g, 1.56 mol) was added, and then nitrogen gas was bubbledthrough the solution vigorously for 20 minutes. Palladium on activatedcarbon (20 g, 10 wt % dry basis) was added and the reaction mixture washeated at 40° C. for 12 hours, and then filtered through a pad ofCelite. The solvent was then removed under reduced pressure and 1M HCl(40 mL) was added to the crude residue. The pH of the mixture was thenadjusted with 10 N NaOH to pH 12. The aqueous layer was extracted withEtOAc (2×150 mL) and the organic layer was dried (magnesium sulfate),filtered and the solvent removed under reduced pressure to give 155 g ofthe title intermediate (100% yield). HPLC (10-70) R_(t=)2.52; m/z:[M+H⁺] calcd for C₁₈H₂₀N₂O₂, 297.15. Found, 297.3.

Preparation 4 N-Benzyl-N-methylaminoacetaldehyde

To a 3-necked 2-L flask was added N-benzyl-N-methylethanolamine (30.5 g,0.182 mol), DCM (0.5 L), DIPEA (95 mL, 0.546 mol) and DMSO (41 mL, 0.728mol). Using an ice bath, the mixture was cooled to about −10° C. andsulfur trioxide pyridine-complex (87 g, 0.546 mol) was added in 4portions over 5 minute intervals. The reaction was stirred at −10° C.for 2 hours. Before removing the ice-bath, the reaction was quenched byadding water (0.5 L). The aqueous layer was separated and the organiclayer was washed with water (0.5 L) and brine (0.5 L) and then driedover magnesium sulfate and filtered to provide the title compound whichwas used without further purification.

Preparation 5 Biphenyl-2-ylcarbamic Acid1-[2-(Benzylmethylamino)ethyl]piperidin-4-yl Ester

To a 2-L flask, containing N-benzyl-N-methylaminoacetaldehyde in DCM(0.5 L; prepared as described in Preparation 4) was addedbiphenyl-2-ylcarbarnic acid piperidin-4-yl ester (30 g, 0.101 mol;prepared as described in Preparation 3) followed by Na(OAc)₃BH (45 g,0.202 mol). The reaction mixture was stirred overnight and then quenchedby the addition of 1 N HCl (0.5 L) with vigorous stirring. Three layerswere observed and the aqueous layer was removed. After washing with 1NNaOH (0.5 L), a homogenous organic layer was obtained which was thenwashed with a saturated solution of aqueous NaCl (0.5 L), dried overmagnesium sulfate, filtered and the solvent removed under reducedpressure. The residue was purified by dissolving it in a minimal amountof isopropanol and cooling this solution to 0° C. to form a solid whichwas collected and washed with cool isopropanol to provide 42.6 g of thetitle compound (95% yield). MS m/z: [M+H⁺] calcd for C₂₈H₃₃N₃O₂, 444.3.Found, 444.6. R_(f)=3.51 min (10-70 ACN:H₂O, reverse phase HPLC).

Preparation 5A

Alternately, the title compound was prepared by mesylation ofN-benzyl-N-methyl ethanolamine, which was then reacted withbiphenyl-2-ylcarbamic acid piperidin-4-yl ester in an alkylationreaction.

A 500 mL flask (reactor flask) was charged withN-benzyl-N-methylethanolamine (24.5 mL), DCM (120 mL), NaOH (80 mL; 30wt %) and tetrabutylammonium chloride. Mixing at low speed throughoutthe reaction, the mixture was cooled to −10° C. (cooling bath), and theaddition funnel charged with DCM (30 mL) and mesyl chloride (15.85 mL),which was added drop wise at a constant rate over 30 minutes. Theaddition was exothermic, and stirring was continued for 15 minutes whilethe temperature equilibrated back to −10° C. The reaction was held forat least 10 minutes to ensure full hydrolysis of the excess mesylchloride.

A 250 mL flask was charged with biphenyl-2-ylcarbamic acidpiperidin-4-yl ester (26 g; prepared as described in Preparation 3) andDCM (125 mL), stirred for 15 minutes at room temperature, and themixture chilled briefly to 10° C. to form a slurry. The slurry was thencharged into the reactor flask via the addition funnel. The cooling bathwas removed and the reaction mixture was warmed to 5° C. The mixture wastransferred to a separatory funnel, the layers allowed to settle, andthe aqueous layer removed. The organic layer was transferred back to thereactor flask, stirring resumed, the mixture held to room temperature,and the reaction monitored by HPLC for a total of 3.5 hours.

The reactor flask was charged with NaOH (1M solution; 100 mL), stirred,and the layers allowed to settle. The organic layer was separated,washed (NaCl satd. solution), its volume partially reduced under vacuum,and subjected to repeated IPA washings. The solids were collected andallowed to air-dry (25.85 g, 98% purity). Additional solids wereobtained from further processing of the mother liquor (volume reduction,IPA, cooling).

Preparation 6 Biphenyl-2-ylcarbamic Acid1-(2-Methylaminoethyl)piperidin-4-yl Ester

To a Parr hydrogenation flask was added biphenyl-2-ylcarbamic acid1-[2-(benzylmethylamino)ethyl]piperidin-4-yl ester (40 g, 0.09 mol;prepared as described in Preparation 5) and EtOH (0.5 L). The flask wasflushed with nitrogen gas and palladium on activated carbon (15 g, 10 wt% dry basis, 37% wt/wt) was added along with HOAc (20 mL). The mixturewas kept on the Parr hydrogenator under a hydrogen atmosphere (˜50 psi)for 3 hours. The mixture was then filtered and washed with EtOH. Thefiltrate was condensed and the residue was dissolved in a minimal amountof DCM. Isopropyl acetate (10 volumes) was added slowly to form a solidwhich was collected to provide 22.0 g of the title compound (70% yield).MS m/z: [M+H⁺] calcd for C₂₁H₂₇N₃O₂, 354.2. Found, 354.3. R_(f)=2.96 min(10-70 ACN:H₂O, reverse phase HPLC).

Preparation 7 Biphenyl-2-ylcarbamic acid1-(2-{[3-(2-tert-butoxycarbonylaminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylester

To a solution of N-(2-tert-butoxycarbonylaminoethyl)isophthalamic acid(9.35 g, 30.3 mmol; prepared as described in Preparation 2) andbiphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester(9.64 g, 27.3 mmol, 0.9 eq; prepared as described in Preparation 6) in150 mL of DCM was added EDCI (6.98 g, 36.4 mmol, 1.2 eq) followed by15.8 mL of DIPEA (91.0 mmol, 3.0 eq). At this point, HPLC analysis wasconducted to ascertain the extent of reaction. Following overnightstirring, the reaction was concentrated under vacuum and taken up in 200mL DCM. The mixture was then washed twice with 150 mL aqueous saturatedNaHCO₃, once with 150 mL brine and 5 times with 200 mL of a 1:1 solutionof 1.0 N HCl in brine to remove any residual ester. The organic phasewas then dried over Na₂SO₄, filtered and concentrated. 20.15 g of crudeproduct was obtained as a white foam solid and used in the next stepwithout further purification.

For large scale synthesis, the reaction was carried out in DCM in thepresence of EDCI (1.2 eq), HOBT (1.2 eq) and DIPEA (3 eq) for 16 hoursat room temperature and 5 hours at reflux.

Preparation 7A

Alternately, the title compound was prepared by acylation of3-acetylbenzoic acid with biphenyl-2-ylcarbamic acid1-(2-methylaminoethyl)piperidin-4-yl ester, which then underwentoxidation, followed by an N-acylation step.

3-carboxybenzaldehyde (4.07 g, 27.11 mmol, 1 eq), HATU (10.307 g, 27.11mmol, 1 eq) and biphenyl-2-ylcarbamic acid1-(2-methylaminoethyl)piperidin-4-yl ester (9.58 g, 27.11 mmol, 1 eq;prepared as described in Preparation 6) were dissolved in a solution ofDCM (100 mL) and DMF (10 mL). DIPEA (14 mL, 81.33 mmol, 3 eq) was addedportionwise and the solution was allowed to stir at room temperature.The reaction mixture was concentrated under vacuum, yielding a yellowoil (34.1 g). The crude oil was dissolved in DCM and washed withH₂O:brine (3×, 200 mL) and with brine (1×). The organic layer wasconcentrated under vacuum to afford biphenyl-2-ylcarbamic acid1-{2-[(3-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester as ayellow foam (13.165 g, 98%):

This aldehyde was oxidized toN-{2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}-N-methylisophthalamicacid using sulfamic acid (3.95 g, 40.65 mmol, 1.5 eq) and NaClO₂ (4.6 g,40.65 mmol, 1.5 eq, dissolved in 20 mL of H₂O) in glacial acetic acid(35 mL) at 0° C. for 40 minutes and at room temperature for 1 hour.After workup, the crude acid was obtained as an orange semi-solid (18.51g):

This acid was then coupled with t-butyl n-(2-aminoethyl)carbamate toyield the title compound.

Preparation 8 Biphenyl-2-ylcarbamic Acid1-(2-{[3-(2-Aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylEster

To a solution of the product of Preparation 7 (20.15 g) in 20 mL DCM wasadded 30 mL TFA in 40 mL DCM. The reaction was stirred at roomtemperature for 1 hour, followed by concentration under high vacuumusing toluene for azeotroph. The crude product was taken up in 200 mLDCM and washed twice with 200 mL solutions of 1:1 brine and 1.0 N NaOH.Additional 1.0 N NaOH was added to achieve a pH of 10. The organic phasewas lastly washed with 200 mL brine, dried over Na₂SO₄, filtered andconcentrated. 16.8 g of the title compound was obtained as an off-whitesolid in 98% yield. MS m/z: [M+H⁺] calcd for C₃₁H₃₇N₅O₄, 544.28. Found544.2.

Example 1 Biphenyl-2-ylcarbamic Acid1-[2-({3-[2-(4-Hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylEster

A solution of biphenyl-2-ylcarbamic acid1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and4-hydroxybenzaldehyde10,411,879 (2.30 g, 18.8 mmol, 1.1 eq) in 125 mLMeOH was stirred at room temperature for 2 hours. Na(OAc)₃BH (7.26 g,34.2 mmol, 2.0 eq) was added to the reaction at room temperature in twoportions separated in one hour interval. The reaction was stirred for anadditional hour before being concentrated under vacuum. The residue wastaken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour.The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixturewas stirred for an additional 10 minutes. The organic phase wasseparated, dried over Na₂SO₄, filtered and concentrated under vacuum.The crude material was purified using silica gel chromatography (7% MeOHin CH₂Cl₂ with 1% NH₄OH as eluent). The title compound was obtained asan off-white solid (8.08 g, 73%). MS m/z: [M+H⁺] calcd for C₃₈H₄₃N₅O₅,650.34. Found, 650.2.

Diacetate Salt Crystal

The ester (1.004 g, 1.538 mmol; prepared as described above) wasdissolved in 2 mL of MeOH/ACN (1:1). The solution was sonicated andheated until completely clear. To the clear solution was added HOAc (174μL, 3.06 mmol) and mixed thoroughly with vortex action. Additional ACN(˜10 mL) was added drop-wise until the solution turned cloudy. Theresulting solution was heated until clear and allowed to sit at roomtemperature overnight to form white crystalline material. The solid wasfiltered, washed with ACN (3×10 mL) and dried under vacuum to give thediacetate salt as a white crystalline solid (900 mg, 76%). The diacetatesalt can then be used to provide a further purified freebase by atwo-step reaction with saturated NH₄HCO₃ and MeOH. Crude free basehaving 91% purity was treated with HOAc and MeOH/ACN to yield adiacetate salt having approximately 97% purity, which was then treatedwith saturated NH₄HCO₃ and MeOH to yield a pure free base having 98+%purity.

A PXRD patterns was obtained with a Rigaku diffractometer using Cu Kα(30.0 kV, 15.0 mA) radiation, and the analysis performed with thegoniometer running in continuous-scan mode of 3° per minute with a stepsize of 0.03° over a range of 2 to 45°. Samples were prepared on quartzspecimen holders as a thin layer of powdered material. The instrumentwas calibrated with a silicon metal standard. The crystalline diacetatesalt is characterized by a PXRD pattern in which the peak positions aresubstantially in accordance with those shown in FIG. 1. Those peaks arelisted below, in order of descending relative intensity.

I % 2-Theta 100 9.771 73.4 17.874 71.9 19.522 30.3 23.723 26.4 23.15023.2 22.191 22 7.372 21.4 26.600 12.5 14.454 11.1 25.939 10.4 24.708 9.910.910 9.5 29.001 8.5 4.969 7.6 18.745 6.7 11.658 6.1 21.291 5.5 30.7935.2 27.296 4.8 20.610 4.8 34.850 4.1 31.642 3.9 13.491 3.8 15.893 3.333.026 2.4 37.583Thus, in one embodiment, the crystalline diacetate salt of the presentinvention is characterized by a powder x-ray diffraction (PXRD) patternhaving two or more diffraction peaks at 2θ values selected from4.97±0.20, 7.37±0.20, 9.77±0.20, 10.91±0.20, 11.66±0.20, 13.49±0.20,14.45±0.20, 15.89±0.20, 17.87±0.20, 18.75±0.20, 19.52±0.20, 20.61±0.20,21.29±0.20, 22.19±0.20, 23.15±0.20, 23.72±0.20, 24.71±0.20, 25.94±0.20,26.60±0.20, 27.30±0.20, 29.00±0.20, 30.79±0.20, 31.64±0.20, 33.03±0.20,34.85±0.20, and 37.58±0.20; and in a specific embodiment, thiscrystalline form is characterized by a powder x-ray diffraction patterncomprising diffraction peaks at 2θ values of 4.97±0.20, 7.37±0.20,9.77±0.20, 10.91±0.20, 14.45±0.20, 17.87±0.20, 18.75±0.20, 19.52±0.20,22.19±0.20, 23.15±0.20, 23.72±0.20, 24.71±0.20, 25.94±0.20, 26.60±0.20,and 29.00±0.20.

DSC was performed using a TA Instruments Model Q-10 module with aThermal Analyst controller, and data were collected and analyzed usingTA Instruments Thermal Solutions software. A sample of about 1 mg of thecrystalline diacetate salt was accurately weighed into an aluminum panwith lid, and evaluated using a linear heating ramp of 10° C./min fromambient temperature to approximately 300° C. The DSC cell was purgedwith dry nitrogen during use. A representative DSC trace for this saltis shown in FIG. 2 and depicts one transition at about 114° C., nothermal decomposition below about 160° C., and maximum endothermic heatflow at about 112° C. This diacetate salt had a melting point of about114° C.

TGA was performed using a TA Instruments Model Q-50 module equipped withhigh resolution capability, and data were collected and analyzed usingTA Instruments Thermal Solutions software. A sample of the crystallinediacetate salt weighing about 2 mg was placed onto a platinum pan andscanned with a high resolution-heating rate from ambient temperature to300° C. The balance and furnace chambers were purged with nitrogen flowsduring use. A representative TGA trace for this salt is shown in FIG. 2and shows a loss of solvents and/or water (9%) at temperatures belowabout 115° C.

Ion analysis of the crystalline diacetate salt determined 15.3% w/wacetate (calculated value: 15.6% w/w).

A dynamic moisture sorption (DMS) assessment (also known as a moisturesorption-desorption profile) was performed for samples of thecrystalline diacetate salt using a VTI atmospheric microbalance, SGA-100system (VTI Corp., Hialeah, Fla. 33016). A sample size of approximately10 mg was used and the humidity was set at the ambient value at thestart of the analysis. A typical DMS analysis consisted of three scans:ambient to 2% relative humidity (RH), 2% RH to 90% RH, 90% RH to 5% RHat a scan rate of 5% RH/step. The mass was measured every two minutesand the RH was changed to the next value (+/−5% RH) when the mass of thesample was stable to within 0.01% for 5 consecutive points. Arepresentative DMS trace for a sample of this crystalline salt showed areversible sorption/desorption profile with less than about 18% weightgain when exposed to up to 90% RH.

Monooxalate Salt Crystal

The ester (1 g, 1.54 mmol; prepared as described above) was dissolved in1 mL of MeOH/ACN (1:1). The solution was sonicated until completelyclear. To the solution was added oxalic acid in EtOH (1M, 1.54 mL, 1 eq)followed by ACN until the solution became cloudy (˜8 mL). The cloudysolution was stirred at 50° C. for 1.5 hours and slowly cooled to roomtemperature under stirring. The solid was filtered, washed with ACN (5mL×3) and dried under high vacuum to give the monooxalate salt as awhite crystalline solid (0.8 g, 70%).

The crystalline monooxalate salt is characterized by a PXRD pattern inwhich the peak positions are substantially in accordance with thoseshown in FIG. 3. Those peaks are listed below, in order of descendingrelative intensity.

I % 2-Theta 100 6.448 86.1 20.582 78.9 11.039 74 27.571 67.8 18.120 62.123.042 53.7 25.620 46.3 24.032 36.7 12.866 36.3 15.420 32.3 14.760 24.519.379 24.1 21.721 23.1 34.324 21.1 13.683 20 12.390 19 9.121 16.832.274 13.7 35.546 11.3 37.855 9.9 32.632 8.7 36.739Thus, in one embodiment, the crystalline monooxalate salt of the presentinvention is characterized by a powder x-ray diffraction (PXRD) patternhaving two or more diffraction peaks at 2θ values selected from6.45±0.20, 9.121±0.20, 11.04±0.20, 12.39±0.20, 12.87±0.20, 13.68±0.20,14.76±0.20, 15.42±0.20, 18.12±0.20, 19.38±0.20, 20.58±0.20, 21.72±0.20,23.04±0.20, 24.03±0.20, 25.62±0.20, 27.57±0.20, 32.27±0.20, 32.63±0.20,34.32±0.20, 35.55±0.20, 36.74±0.20, and 37.86±0.20; and in a specificembodiment, this crystalline form is characterized by a powder x-raydiffraction pattern comprising diffraction peaks at 2θ values of6.45±0.20, 11.04±0.20, 12.87±0.20, 13.68±0.20, 14.76±0.20, 15.42±0.20,18.12±0.20, 19.38±0.20, 20.58±0.20, 21.72±0.20, 23.04±0.20, 24.03±0.20,25.62±0.20, 27.57±0.20, and 34.32±0.20. A representative DSC trace ofthe crystalline monooxalate salt is shown in FIG. 4 and depicts onetransition at about 133° C., and no thermal decomposition below about150° C. FIG. 4 also depicts a representative TGA trace of this salt,which shows a loss of solvents and/or water (2%) at temperatures belowabout 170° C. Ion analysis of this crystalline salt determined 11.86%w/w oxalate (calculated value: 12.16% w/w). A representative DMS tracefor a sample of this crystalline salt showed a reversiblesorption/desorption profile with less than about 14% weight gain whenexposed to up to 90% RH. This monooxalate salt had a melting point ofabout 134° C.

Dipropionate Salt Crystal

The ester (107 mg, 0.165 mmol; prepared as described above) wasdissolved in 4 mL of ACN. The solution was sonicated and heated untilcompletely clear. Propionic acid (25 μL, 0.33 mmol) was added to thesolution and the solution turned to cloudy. MeOH (50 mL) was added inand the solution was stirred at 50° C. until it was completely clear.The solution was slowly cooled down to room temperature and stirredovernight to form a white crystalline material. The solid was filtered,washed with ACN (0.5 mL×3) and dried under vacuum to give thedipropionate salt as a white crystalline solid (82.3 mg, 63%).

The crystalline dipropionate salt is characterized by a PXRD pattern inwhich the peak positions are substantially in accordance with thoseshown in FIG. 5. Those peaks are listed below, in order of descendingrelative intensity.

I % 2-Theta 100 10.108 91.2 9.691 84.9 19.381 82 18.751 69.4 23.012 66.820.218 65.4 14.850 59.6 24.063 48 21.659 41.7 7.201 34.6 16.889 31.824.479 29.2 11.338 24.8 21.234 24.5 30.125 19.3 27.781 16.7 27.090 1528.348 14.3 20.553 13.9 29.107 13.6 5.007 13.4 22.418 12.9 38.968 12.315.420 11.7 26.364 10.9 11.759 10.5 30.719 10.5 31.775 10.3 34.676 9.337.381 7.9 32.482 6.6 35.604 5.8 39.294 5.5 33.894 4.8 36.954Thus, in one embodiment, the crystalline dipropionate salt of thepresent invention is characterized by a powder x-ray diffraction (PXRD)pattern having two or more diffraction peaks at 2θ values selected from5.01±0.20, 7.20±0.20, 9.69±0.20, 10.11±0.20, 11.34±0.20, 11.76±0.20,14.85±0.20, 15.42±0.20, 16.89±0.20, 18.75±0.20, 19.38±0.20, 20.22±0.20,20.55±0.20, 21.23±0.20, 21.66±0.20, 22.42±0.20, 23.01±0.20, 24.06±0.20,24.48±0.20, 26.36±0.20, 27.09±0.20, 27.78±0.20, 28.35±0.20, 29.11±0.20,30.13±0.20, 30.72±0.20, 31.78±0.20, 32.48±0.20, 33.89±0.20, 34.68±0.20,35.60±0.20, 36.95±0.20, 37.38±0.20, 38.97±0.20, and 39.29±0.20; and in aspecific embodiment, this crystalline form is characterized by a powderx-ray diffraction pattern comprising diffraction peaks at 2θ values of7.20±0.20, 9.69±0.20, 10.11±0.20, 11.34±0.20, 14.85±0.20, 16.89±0.20,18.75±0.20, 19.38±0.20, 20.22±0.20, 21.23±0.20, 21.66±0.20, 23.01±0.20,24.06±0.20, 24.48±0.20, and 30.13±0.20. A representative DSC trace ofthe crystalline dipropionate salt is shown in FIG. 6 and depicts onetransition at about 100° C., no thermal decomposition below about 150°C., and maximum endothermic heat flow at about 99° C. This dipropionatesalt had a melting point of about 100° C. FIG. 6 also depicts arepresentative TGA trace of this salt, which shows a loss of solventsand/or water (5%) at temperatures below about 100° C. Ion analysis ofthis crystalline salt determined 18.85% w/w propionate (calculatedvalue: 18.5% w/w). A representative DMS trace for a sample of thiscrystalline salt showed a reversible sorption/desorption profile withless than about 11% weight gain when exposed to up to 90% RH.

Hemiedisylate Salt Crystal

The ester (1.07 g, 1.66 mmol amorphous freebase; prepared as describedabove) was dissolved in a round bottom flask in a solvent mixture of 20%MeOH and 80% ACN (10 mL). A free acid solution of 1,2 ethane disulfonicacid (½ equivalent of acid, 0.19 g, 0.83 mmol) was dissolved in the samesolvent system (20% MeOH, 80% ACN, 1 mL). The acid solution was addeddrop wise to the freebase solution over 10 minutes, while stirring atapproximately 22° C. Once the acid was completely fed to the flask, theliquor appeared cloudy-white. The liquor was heated to 50° C. forone-half hour, then slowly cooled to 22° C. Agitation was continued for2 hours to enable greater recovery and growth of the crystals. Thecrystals were recovered from the slurry by vacuum filtration, and thecake was washed with ACN (1 mL×3), followed by vacuum drying. The yieldwas 87.6% with respect to the freebase starting material. HPLC, XRPD,NMR and ion analysis confirmed this was a crystalline hemiedisylatesalt.

Heminapadisylate Methanolate Crystal

The ester (18.87 g, 29.04 mmol, 98.57% pure amorphous freebase; preparedas described above) was dissolved in a solvent mixture of 20% MeOH and80% ACN (250 mL). 1,5 naphthalene disulfonic acid (½ mole equivalent,4.573 g, 3.97 mmol) was dissolved in 170 mL of equivalent solventmixture. The acid went into solution after vigorous sonication (heatingcould alternately be used to speed dissolution of the acid). The overallsalt mass to solvent volume ratio was 1:18. The freebase solution wasplaced in round bottom flask, in a large oil bath. To the freebasesolution, the acid solution was added drop wise via an addition funnel,while stirring at room temperature. The acid feed rate was approximately5 mL per minute. After adding approximately 75 mL of the acid solutionthe reaction mixture was heated to 30° C. The mixture became partiallycloudy at this temperature. After addition of the 170 mL of acid, thesolution was heated to 50° C. The mixture was stirred at 50° C. forone-half hour before it was slowly cooled to room temperature, whilestirring over night. Over this period, crystallization occurred. Thesolid was filtered, washed with a solvent mixture containing 10%MeOH/90% ACN (100 mL×3) and a yield of 84% was obtained (freebaseequivalent).

Heminapadisylate Ethanolate Crystal

A solid mixture of the ester (75 mg amorphous freebase; prepared asdescribed above) and crystalline 1,5 naphthalene disulphonic acid (20.3mg) was prepared in a 15 mL vial. The solids were dissolved by adding2.5 mL of EtOH and heating to 40° C. for 5 minutes. Crystallization wasinduced by adding 2.5 mL of ACN and cooling to room temperature(approximately 22° C.) and leaving over night. Large birefringent wellformed solid particles were obtained. These solids were analyzed bysingle crystal X-ray diffraction and found to be crystallineheminapadisylate ethanolate ester.

Heminapadisylate Salt Crystal

Crystalline heminapadisylate methanolate, prepared as described above,was converted to the desolvated crystal form of the ester by thefollowing procedure: The filter cake was dried in a vacuum oven at 50°C., with a purging nitrogen flow, overnight, then at 40° C. over 3 days.19.75 g of the heminapadisylate salt was obtained as a white crystallinesolid (84% yield freebase equivalent).

Alternately, the desolvated crystal form was prepared by heating thecrystalline heminapadisylate methanolate form in a vacuum oven at 100°C., with a purging nitrogen flow for 4 hours.

Alternately, the desolvated crystal form was prepared reslurrying thecrystalline heminapadisylate methanolate form in an excess of ACN(approximately 1-5% solids concentration) at 22° C. for two to fourdays.

Freebase Crystal (Polymorph Form I)

The ester (20 g amorphous freebase; prepared as described in Example 1)was dissolved in 200 mL of EtOAc and 60 mL of IPA room temperature. Thesolution was washed with water 2×100 mL. The organic phase was driedover MgSO4 then filtered. A small amount of crystals (90 mg) formedafter filtration. The crystals were collected and dried under highvacuum.

Freebase Crystal (Polymorph Form II)

A 200 mg/mL solution was prepared by dissolving 50 mg of the ester(amorphous freebase; prepared as described above) in 0.25 mL of IPA at22° C. in a glass HPLC vial. After two days, the vial was inspected bystereozoom microscope under polarized light. Birefringent particles wereobserved, indicating a crystalline morphology. After 7 days from initialdissolution, inspection of the vial found that crystals had continued togrow. The mother liquor was decanted and the crystals were washed withapproximately 100-200 μL of 1:1 IPA:water. This material was confirmedto be crystalline by PXRD.

A larger batch was prepared for further characterization, by dissolving200 mg of the amorphous freebase ester (prepared as described inExample 1) into 1.0 mL of IPA and 20 μL of water (2% vol/vol), at 22° C.Approximately 1-3 mg of seed crystals from the initial batch was addedto the vial. The vial was left at 22° C. overnight, then inspected bystereozoom microscopy with crossed polarizing filters. Birefringent wellformed crystals were observed covering the base of the vial). These werefurther crystallized by cooling at 4° C., before isolation andcharacterization. HPLC analysis confirmed that the crystalline solid wasconsistent with the retention time of the parent compound (amorphousfreebase ester) and the crystals had a purity of 98.6%, while the motherliquor purity was 96.7%. The amorphous feed material had a purity of98.4%. Hence there was some purification achieved by crystallization ofthe freebase ester.

Example 2

Following the procedure described in Example 1 and substituting theappropriate starting materials and reagents, the following compoundswere prepared.

    #     Name     R⁴

2-1 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(4-hydroxy-3-methoxybenzylamino) ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₉H₄₅N₅O₆, 680.35; found, 680.4. Me

2-2 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoyl}ethylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₈H₄₃N₅O₅, 650.34; found, 650.4. Me

2-3 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoyl}ethylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₉H₄₅N₅O₅, 664.35; found, 664.4. Me

2-4 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-hydroxy-2-methoxybenzylamino)ethylcarbamoyl]benzoyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₈H₄₃N₅O₆, 666.33; found, 666.2. H

2-5 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl] benzoyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.2. H

2-6 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-methoxybenzylamino)ethylcarbamoyl] benzoyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₈H₄₃N₅O₅, 650.34; found, 650.2. H

2-7 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₈H₄₃N₅O₅, 650.34; found, 650.4. Me

2-8 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3-hydroxy-4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₉H₄₅N₅O₆, 680.35; found, 680.4. Me

2-9 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3,4-dihydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₈H₄₃N₅O₆, 666.33; found, 666.4. Me

Example 3

Compound 3-3 was prepared as follows: To a solution ofbiphenyl-2-ylcarbamic acid1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylester (55 mg, 0.1 mmol; prepared as described in Preparation 8) in 1 mLof MeOH was added the appropriated aldehyde (0.1 mmol) at roomtemperature. The reaction was stirred at room temperature for 30 minutesbefore it was treated with Na(OAc)₃BH (64 mg, 0.3 mmol). Stirring wascontinued for an additional 1 hour. The reaction mixture wasconcentrated, then dissolved in 1 mL of 1:1 HOAc/water solution andpurified on reverse phase HPLC. Compound 3-3 was obtained as atri(trifluoroacetate) salt, while compound 3-4 was isolated as a byproduct.

Compounds 3-1 and 3-2 were also prepared by following a similarprocedure and substituting the appropriate aldehyde.

  #   Name

3-1 Biphenyl-2-ylcarbamic acid 1-{2-[methyl(3-{2-[(thiophen-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)amino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₆H₄₁N₅O₄S, 640.30; found, 640.2.

3-2 Biphenyl-2-ylcarbamic acid 1-{2-[(3-{2-[(furan-2-ylmethyl)amino]ethylcarbamoyl}benzoyl) methylamino]ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₁N₅O₅, 624.32; found, 624.2.

3-3 Biphenyl-2-ylcarbamic acid 1-{2-[(3-{2-[(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₅H₄₁N₇O₄, 624.33; found, 624.4.

3-4 Biphenyl-2-ylcarbamic acid 1-{2-[(3-{2-[bis-(1H-imidazol-2-ylmethyl)amino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₉H₄₅N₉O₄, 704.37.

Example 4

Following the procedures described in the previous examples, andsubstituting the appropriate starting materials and reagents, thefollowing compounds were prepared.

# Name Y 4-1 Biphenyl-2-ylcarbamic acid 1-[2-({5-[2-(4-hydroxybenzylamino)ethylcarbamoyl] thiophene-2-carbonyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₆H₄₁N₅O₅S, 656.29; found, 656.2.

4-2 Biphenyl-2-ylcarbamic acid 1-{2-[methyl-(5-{2-[(pyridin-4-ylmethyl)amino]ethylcarbamoyl}thiophene-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₅H₄₀N₆O₄S, 641.29; found, 641.2.

Example 5

To a solution of compound A (R⁴=H, 1 g, 2.95 mmol) and 3-nitrobenzoicacid (0.59 g, 3.54 mmol) in DCM (30 mL) were added EDCI (0.85 g, 4.43mmol), HOBT (0.6 g, 4.43 mmol) and DIPEA (1 mL, 5.9 mmol). The reactionwas stirred at room temperature overnight before it was taken up in 50mL of DCM. The mixture was washed with water 2×100 mL. Organic phase wasdried over MgSO₄ and concentrated to give crude compound B (R⁴=H) as apale yellow solid in quantitative yield:

The solution of compound B (R⁴=H, 1.45 g, 2.95 mmol) in 100 mL MeOH wasstirred under H₂ atmosphere in the presence of Pd catalyst (10% Pd/C,300 mg) at room temperature for overnight. The catalyst was removed byfiltration and the solvent was concentrated to give crude C (R⁴=H, 1.46g, 108%) as an off-white solid.

To the solution of compound C(R⁴=H, 243 mg, 0.53 mmol) in 5 mL of DCMwas added 3-chloropropionyl chloride (compound D, r=1; 0.066 mL, 0.69mmol) followed by DIPEA (0.276 mL, 1.59 mmol). The reaction was stirredat room temperature for 2 hours before it was concentrated. The residuewas dissolved in ACN (6 mL). An aliquot (1 mL) of the solution wastreated with 4-hydroxybenzylamine (2 mmol) at 50° C. for 3 hours. Thereaction was concentrated and purified via HPLC to give compound 5-1 asa bis(trifiuoroacetate) salt.

Compounds 5-2 to 5-7 were prepared by following a similar procedure andsubstituting the appropriate starting materials and reagents.

    #     Name     R⁴     r

5-1 Biphenyl-2-ylcarbamic acid 1-(2-{3-[3-(4-hydroxybenzylamino)propionylamino] benzoylamino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.4. H 1

5-2 Biphenyl-2-ylcarbamic acid 1-[2-(3-{3-[2-(4-hydroxyphenyl)ethylamino]propionylamino} benzoylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₄₃N₅O₅, 650.34;found, 650.2. H 1

5-3 Biphenyl-2-ylcarbamic acid 1-[2-({3-[3-(4-hydroxybenzylamino)propionylamino]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₈H₄₃N₅O₅, 650.34; found, 650.2. Me 1

5-4 Biphenyl-2-ylcarbamic acid 1-{2-[(3-{3-[2-(4-hydroxyphenyl)ethylamino]propionylamino} benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₉H₄₅N₅O₅,664.35; found, 664.2. Me 1

5-5 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(4-hydroxybenzylamino)acetylamino] benzoyl}methylamino)ethyl]piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.4. Me 0

5-6 Biphenyl-2-ylcarbamic acid 1-{2-[(3-{2-[2-(4-hydroxyphenyl)ethylamino] acetylamino}benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₄₃N₅O₅, 650.34;found, 650.2. Me 0

5-7 Biphenyl-2-ylcarbamic acid 1-[2-(3-{2-[2-(4-hydroxyphenyl)ethylamino] acetylamino}benzoylamino)ethyl] piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.2. H0

Example 6

Following the procedures described in the previous examples andsubstituting the appropriate starting materials and reagents, thefollowing compounds were prepared.

    #     Name

6-1 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-hydroxybenzylamino)ethylcarbamoyl] phenylcarbamoyl} ethyl)piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.2.

6-2 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-hydroxy-3-methoxybenzylamino)ethylcarbamoyl]phenyl carbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₄₃N₅O₆, 666.33;found, 666.2.

6-3 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]phenylcarbamoyl} ethyl)piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.2.

Example 7

Following the procedures described in the proceeding examples, andsubstituting the appropriate starting materials and reagents, thefollowing compounds were prepared.

    #     Name

7-1 Biphenyl-2-ylcarbamic acid 1-(2-{3-[3-(4-hydroxybenzylamino)propionylamino]phenyl- carbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32;found, 636.2.

7-2 Biphenyl-2-ylcarbamic acid 1-(2-{3-[3-(4-hydroxy-3-methoxybenzylamino) propionylamino]phenylcarbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₄₃N₅O₆, 666.33;found, 666.2.

7-3 Biphenyl-2-ylcarbamic acid 1-(2-{3-[3-(2-hydroxybenzylamino)propionylamino]phenyl- carbamoyl}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₇H₄₁N₅O₅, 636.32; found, 636.2.

Example 8

Following the procedures described in the previous examples, andsubstituting the appropriate starting materials and reagents, thefollowing compounds were prepared.

    #     Name     R⁴     r

8-1 Biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3-(3-pyrrolidin-1-ylpropionylamino) benzoyl]amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₅H₄₃N₅O₅, 598.34; found, 598.2. Me 1

8-2 Biphenyl-2-ylcarbamic acid 1-{2-[3-(3-pyrrolidin-1-ylpropionylamino) benzoylamino]ethyl}piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₄H₄₁N₅O₄, 584.33; found, 584.4. H 1

8-3 Biphenyl-2-ylcarbamic acid 1-[2-({3-[3- (4-carbamoylpiperidin-1-yl)propionylamino]benzoyl}methylamino) ethyl]piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₇H₄₆N₆O₅, 655.36; found, 655.4. Me 1

8-4 Biphenyl-2-ylcarbamic acid 1-(2-{3-[3- (4-carbamoylpiperidin-1-yl)propionylamino]benzoylamino}ethyl) piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₆H₄₄N₆O₅, 641.35; found, 641.2. H 1

8-5 Biphenyl-2-ylcarbamic acid 1-(2-{methyl[3-(2-pyrrolidin-1-yl-acetylamino) benzoyl]amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₁N₅O₄, 584.33; found, 584.2. Me 0

8-6 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(4-hydroxypiperidin-1-yl)acetylamino]benzoyl}methylamino)ethyl]piperidin-4- yl ester. MS m/z: [M + H⁺] calcdfor C₃₅H₄₃N₅O₅, 614.34; found, 614.4. Me 0

8-7 Biphenyl-2-ylcarbamic acid 1-{2-[3-(2- pyrrolidin-1-ylacetylamino)benzoylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₃H₃₉N₅O₄, 570.31; found, 570.2. H 0

8-8 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-hydroxypiperidin-1-yl)acetylamino] benzoylamino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₁N₅O₅, 560.32; found, 600.2. H 0

8-9 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(4-carbamoylpiperidin-1-yl)acetylamino]benzoylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₅H₄₂N₆O₅, 627.33; found, 627.2. H 0

Example 9

Following the procedures described in the previous examples, andsubstituting the appropriate starting materials and reagents, thefollowing compounds were prepared.

  #   Name   Z²

9-1 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(cyclopropylmethylamino)ethylcarbamoyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₄H₄₁N₅O₄, 584.33; found, 584.2. —C(O)NH—

9-2 Biphenyl-2-ylcarbamic acid 1-(2-{3-[3-(cyclopropylmethylamino)propionylamino]phenylcarbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₄H₄₁N₅O₄, 584.33; found, 584.2. —NHC(O)—

9-3 Biphenyl-2-ylcarbamic acid 1-[2-(3-{2-[(1H-imidazol-2-ylmethyl)amino] ethylcarbamoyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₄H₃₉N₇O₄, 610.32;found 610.4. —C(O)NH—

9-4 Biphenyl-2-ylcarbamic acid 1-[2-(3-{3-[(1H-imidazol-2-ylmethyl)amino] propionylamino}phenylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₄H₃₉N₇O₄, 610.32;found 610.2. —NHC(O)—

9-5 Biphenyl-2-ylcarbamic acid 1-[2-(3-{2- [(furan-2-ylmethyl)amino]ethylcarbamoyl} phenylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₅H₃₉N₅O₅, 610.31; found 610.2. —C(O)NH—

9-6 Biphenyl-2-ylcarbamic acid 1-[2-(3-{3- [(furan-2-ylmethyl)amino]propionylamino} phenylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₅H₃₉N₅O₅, 610.31; found 610.2. —NHC(O)—

Example 10

Following the procedures described in the previous examples, andsubstituting the appropriate starting materials and reagents, thefollowing compounds were prepared.

  #   Name   R⁴   r

10-1 Biphenyl-2-ylcarbamic acid 1-(2-{[3-(3-cyclopropylaminopropionylamino)benzoyl] methylamino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₁N₅O₄, 584.33; found, 584.2. Me 1

10-2 Biphenyl-2-ylcarbamic acid 1-{2-[3-(3-cyclopropylaminopropionylamino)benzoyl amino]ethyl}piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₃H₃₉N₅O₄, 570.31; found, 570.2. H 1

10-3 Biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3-(3- Me 1 —NH(CH₃)methylaminopropionylamino)benzoyl]amino} ethyl)piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₂H₃₉N₅O₄, 578.31; found, 558.2. 10-4Biphenyl-2-ylcarbamic acid 1-{2-[3-(3- H 1 —NH(CH₃)methylaminopropionylamino)benzoylamino] ethyl}piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₄, 544.29; found, 544.2. 10-5Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(2-hydroxyethylamino)acetylamino]benzoyl amino}ethyl)piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₅, 560.29; found, 560.2. H 0

10-6 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(carbamoylmethylamino)acetylamino]benzoyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₁H₃₆N₆O₅, 573.28; found, 573.2. H 0

10-7 Biphenyl-2-ylcarbamic acid 1-[2-(methyl-{3-[2-(3-oxopiperazin-1-yl)acetylamino]benzoyl} amino)ethyl]piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₀N₆O₅, 613.32; found, 613.2. Me 0

10-8 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(cyclopropylmethylamino)acetylamino]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₄H₄₁N₅O₄, 584.33; found, 584.3. Me 0

10-9 Biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3-(2- Me 0 —NH(CH₃)methylaminoacetylamino)benzoyl]amino} ethyl)piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₄, 544.29; found, 544.2. 10-10Biphenyl-2-ylcarbamic acid 1-(2-{[3-(2- Me 0 —NH—(CH₂CH₃)ethylaminoacetylamino)benzoyl]methylamino} ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₂H₃₉N₅O₄, 558.31; found, 558.2. 10-11Biphenyl-2-ylcarbamic acid 1-(2-{[3-(2-cyclopropylaminoacetylamino)benzoyl] methylamino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₃H₃₉N₅O₄, 570.31; found, 570.2. Me 0

10-12 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(2-hydroxyethylamino)acetylamino]benzoyl} methylamino)ethyl]piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₃₉N₅O₅, 574.31; found, 574.2. Me 0

10-13 Biphenyl-2-ylcarbamic acid 1-(2-{3-[2-(cyclopropylmethylamino)acetylamino]benzoyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₃H₃₉N₅O₄, 570.31; found, 570.2. H 0

10-14 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(cyclopropylmethylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₅H₄₃N₅O₄, 598.34; found 598.4. Me 1

10-15 Biphenyl-2-ylcarbamic acid 1-{2-[3-(2- H 0 —NH(CH₃)methylaminoacetylamino)benzoylamino]ethyl} piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₀H₃₅N₅O₄, 530.28; found, 530.2. 10-16Biphenyl-2-ylcarbamic acid 1-{2-[3-(2- H 0 —NH—(CH₂CH₃)ethylaminoacetylamino)benzoylamino] ethyl}piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₁H₃₇N₅O₄, 544.29; found, 544.2. 10-17Biphenyl-2-ylcarbamic acid 1-{2-[3-(2-cyclopropylaminoacetylamino)benzoylamino] ethyl}piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₂H₃₇N₅O₄, 556.29; found, 558.2. H 0

Preparation 9 N-(2,2-Dimethoxyethyl)isophthalamic Acid Methyl Ester

Mono-methyl isophthalate (1 g, 5.55 mmol), amino acetaldehyde dimethylacetal (569 μL, 5.28 mmol) and EDCI (1.52 g, 7.92 mmol) were dissolvedin 55 mL DCM, followed by the addition of DIPEA (1.84 mL, 10.56 mmol).The reaction was allowed to stir at room temperature for 2 hours. It wasthen taken up in 50 mL of DCM, washed with saturated NaHCO₃ solution(100 mL), and brine (100 mL). The organic layer was dried over MgSO₄,filtered and concentrated to afford the crude product (1.48 g) as aclear oil which was used in the next step without further purification.

Preparation 10 N-(2,2-Dimethoxyethyl)isophthalamic Acid

1.48 g of the product of Preparation 9 was dissolved in DMF (5 mL), andNaOH (2.8 mL of 10 N solution, 27.75 mmol) was added. The reaction wasstirred at room temperature overnight. It was then adjusted to pH 5using 1.0 N HCl and extracted with EtOAc 3×50 mL and DCM 3×50 mL. Theorganic phases were combined, dried over MgSO4 and concentrated toafford 0.55 g crude product as an off-white solid which was used in thenext step without further purification.

Preparation 11 Biphenyl-2-ylcarbamic Acid1-(2-{[3-(2,2-Dimethoxyethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-ylEster

To a solution of the product of Preparation 10 (0.55 g, 2.2 mmol) andbiphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester(0.77 g, 2.2 mmol; prepared as described in Preparation 6) in 12 mL ofDCM was added EDCI (0.55 g, 2.86 mmol) followed by 0.77 mL of DIPEA (4.4mmol, 2 eq). After stirring at room temperature for 3 hours, thereaction was taken up in 100 mL DCM. The mixture was then washed with100 mL of a 1:1 solution of 1.0 N HCl in brine, then washed with brine100 mL. The organic phase was then dried over MgSO₄, filtered andconcentrated. The crude product was obtained as a white solid (0.86 g,68%).

Preparation 12 Biphenyl-2-ylcarbamic Acid1-(2-{Methyl-[3-(2-oxoethylcarbamoyl)benzoyl]amino}ethyl)piperidin-4-ylEster

To a solution of the product of Preparation 11 (0.86 g, 1.46 mmol) in 25mL of acetone was added 3 mL of 1 N HCl. The reaction was stirred atroom temperature overnight before it was concentrated under reducedpressure. The residual aqueous solution was lyophilized to give 0.8 g ofcrude product as an off-white solid.

Example 11

Biphenyl-2-ylcarbamic Acid1-(2-{Methyl-[3-(2-methylaminoethylcarbamoyl)benzoyl]amino}ethyl)piperidin-4-ylEster

A solution of the product of Preparation 12 (56 mg, 0.1 mmol) and methylamine (1M in THF, 0.2 mL, 0.2 mmol) in 1 mL of MeOH was stirred at roomtemperature for 1 hour before Na(OAc)₃BH (60 mg, 0.3 mmol) was added tothe reaction. The mixture was allowed to stir for an additional hour andwas concentrated under reduced pressure. The residue was dissolved in1.5 mL of a 1:1 HOAc/H₂O mixture, and was purified by reversed-phaseHPLC to afford the title compound as a bis(trifluoroacetate) salt. MSm/z: [M+H⁺] calcd for C₃₂H₃₉N₅O₄, 558.31. Found, 558.2.

Example 12

Following the procedure described in Example 11 and substituting theappropriate amine in place of methyl amine, the following compounds wereprepared.

# Name Y 12-1 Biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(2- —NH(CH₂CH₂OH)hydroxyethylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₃H₄₁N₅O₅, 588.32; found, 588.2. 12-2 Biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[2-(4- hydroxyphenyl)ethylamino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₉H₄₅N₅O₅, 664.35; found, 664.4.

Example 13

Compound 13-6 was prepared as follows. A solution of terephthalic acid(33 mg, 0.2 mmol), HATU (228 mg, 0,6 mmol) and DIPEA (0.1 mL, 0.6 mmol)in DMF (0.5 mL) was stirred at room temperature for 0.5 hours.Biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester(70.7 mg, 0.2 mmol; prepared as described in Preparation 6) and t-butyln-(2-aminoethyl) carbamate (32 mg, 0.2 mmol) were added to the reactionsequentially in one hour interval. The mixture was then stirred at roomtemperature for an additional 1 hour. Solvent was removed under reducedpressure. The residue was purified by HPLC to give the titled compoundas a bis(trifluoroacetate) salt.

Following the procedure described above and substituting the appropriatearomatic diacid, compounds 13-1 to 13-5 were also prepared.

# Name Ar¹ 13-1 Biphenyl-2-ylcarbamic acid 1-(2-{[6-(2-aminoethylcarbamoyl)pyridine-2-carbonyl]methyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₀H₃₆N₆O₄, 545.28; found 545.2.

13-2 Biphenyl-2-ylcarbamic acid 1-(2-{[5-(2-aminoethylcarbamoyl)pyridine-3-carbonyl]methyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₀H₃₆N₆O₄, 545.28; found 545.2.

13-3 Biphenyl-2-ylcarbamic acid 1-(2-{[6-(2-aminoethylcarbamoyl)pyridine-3-carbonyl]methyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₀H₃₆N₆O₄, 545.28; found 545.2.

13-4 Biphenyl-2-ylcarbamic acid 1-(2-{[5-(2-aminoethylcarbamoyl)thiophene-2-carbonyl]methyl amino}ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₂₉H₃₅N₅O₄S, 550.24; found 550.2.

13-5 Biphenyl-2-ylcarbamic acid 1-(2-{[5-(2-aminoethylcarbamoyl)furan-2-carbonyl]methyl amino}ethyl)piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₂₉H₃₅N₅O₅, 534.26; found 534.2.

13-6 Biphenyl-2-ylcarbamic acid 1-(2-{[4-(2-aminoethylcarbamoyl)benzoyl]methylamino} ethyl)piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₄, 544.28; found 544.2.

Example 14 Biphenyl-2-ylcarbamic Acid1-{2-[3-(2-Aminoethylcarbamoyl)benzoylamino]ethyl}piperidin-4-yl Ester

The title compound was prepared following a similar procedure asdescribed in Example 13, by substituting the appropriatebiphenyl-2-ylcarbamic acid 1-(aminoethyl)piperidin-4-yl ester in placeof biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl esterand substituting isophthalic acid in place of terephthalic acid.

MS m/z: [M+H⁺] calcd for C₃₀H₃₅N₅O₄, 530.27. Found 530.3.

Example 15 Biphenyl-2-ylcarbamic Acid1-(2-{[5-(3-Aminopropylcarbamoyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-ylEster

The title compound was prepared following a similar procedure asdescribed in Example 13, and substituting 2,5-thiophenedicarboxylic acidin place of terephthalic acid, and substituting t-butyln-(3-aminopropyl) carbamate in place of t-butyl n-(2-aminoethyl)carbamate.

MS m/z: [M+H⁺] calcd for C₃₀H₃₇N₅O₄S, 564.26. Found 564.2.

Assay 1 Radioligand Binding Assay Membrane Preparation from CellsExpressing hM₁, hM₂, hM₃ and hM₄ Muscarinic Receptor Subtypes

CHO cell lines stably expressing cloned human hM₁, hM₂, hM₃ and hM₄muscarinic receptor subtypes, respectively, were grown to nearconfluency in medium consisting of HAM's F-12 supplemented with 10% FBSand 250 μg/mL Geneticin. The cells were grown in a 5% CO₂, 37° C.incubator and lifted with 2 mM EDTA in dPBS. Cells were collected by 5minute centriftigation at 650×g, and cell pellets were either storedfrozen at −80° C. or membranes were prepared immediately. For membranepreparation, cell pellets were resuspended in lysis buffer andhomogenized with a Polytron PT-2100 tissue disrupter (Kinematica AG; 20seconds×2 bursts). Crude membranes were centrifuged at 40,000×g for 15minutes at 4° C. The membrane pellet was then resuspended withresuspension buffer and homogenized again with the Polytron tissuedisrupter. The protein concentration of the membrane suspension wasdetermined by the method described in Lowry, O. et al., Journal ofBiochemistry 193:265 (1951). All membranes were stored frozen inaliquots at −80° C. or used immediately. Aliquots of prepared hM₅receptor membranes were purchased directly from Perkin Elmer and storedat −80° C. until use.

Radioligand Binding Assay on Muscarinic Receptor Subtypes hM₁, hM₂, hM₃,hM₄ and hM₅

Radioligand binding assays were performed in 96-well microtiter platesin a total assay volume of 100 μL. CHO cell membranes stably expressingeither the hM₁, hM₂, hM₃, hM₄ or hM₅ muscarinic subtype were diluted inassay buffer to the following specific target protein concentrations(μg/well): 10 μg for hM₁, 10-15 μg for hM₂, 10-20 μg for hM₃, 10-20 μgfor hM₄, and 10-12 μg for hM₅. The membranes were briefly homogenizedusing a Polytron tissue disruptor (10 seconds) prior to assay plateaddition. Saturation binding studies for determining K_(D) values of theradioligand were performed using L-[N-methyl-³H]scopolamine methylchloride ([³H]-NMS) (TRK666, 84.0 Ci/mmol, Amersham Pharmacia Biotech,Buckinghamshire, England) at concentrations ranging from 0.001 nM to 20nM. Displacement assays for determination of K_(i) values of testcompounds were performed with [³H]-NMS at 1 nM and eleven different testcompound concentrations. The test compounds were initially dissolved toa concentration of 400 μM in dilution buffer and then serially diluted5× with dilution buffer to final concentrations ranging from 10 pM to100 μM. The addition order and volumes to the assay plates were asfollows: 25 μL radioligand, 25 μL diluted test compound, and 50 μLmembranes. Assay plates were incubated for 60 minutes at 37° C. Bindingreactions were terminated by rapid filtration over GF/B glass fiberfilter plates (PerkinElmer Inc., Wellesley, Mass.) pre-treated in 1%BSA. Filter plates were rinsed three times with wash buffer (10 mMHEPES) to remove unbound radioactivity. Plates were then air dried, and50 μL Microscint-20 liquid scintillation fluid (PerkinElmer Inc.,Wellesley, Mass.) was added to each well. The plates were then countedin a PerkinElmer Topcount liquid scintillation counter (PerkinElmerInc., Wellesley, Mass.). Binding data were analyzed by nonlinearregression analysis with the GraphPad Prism Software package (GraphPadSoftware, Inc., San Diego, Calif.) using the one-site competition model.K_(i) values for test compounds were calculated from observed IC₅₀values and the K_(D) value of the radioligand using the Cheng-Prusoffequation (Cheng Y; Prusoff W. H. Biochemical Pharmacology22(23):3099-108 (1973)). K_(i) values were converted to pK_(i) values todetermine the geometric mean and 95% confidence intervals. These summarystatistics were then converted back to K_(i) values for data reporting.

In this assay, a lower K_(i) value indicates that the test compound hasa higher binding affinity for the receptor tested. For example, thecompound of Example 1 was found to have a K_(i) value of less than about5 nM for the M₃ muscarinic receptor subtype when tested in this or asimilar assay.

Assay 2 Muscarinic Receptor Functional Potency Assays Blockade ofAgonist-Mediated Inhibition of cAMP Accumulation

In this assay, the functional potency of a test compound is determinedby measuring the ability of the test compound to blockoxotremorine-inhibition of forskolin-mediated cAMP accumulation inCHO-K1 cells expressing the hM₂ receptor.

cAMP assays are performed in a radioimmunoassay format using theFlashplate Adenylyl Cyclase Activation Assay System with ¹²⁵I-cAMP (NENSMP004B, PerkinElmer Life Sciences Inc., Boston, Mass.), according tothe manufacturer's instructions.

Cells are rinsed once with dPBS and lifted with Trypsin-EDTA solution(0.05% trypsin/0.53 mM EDTA) as described in the Cell Culture andMembrane Preparation section above. The detached cells are washed twiceby centrifugation at 650×g for five minutes in 50 mLs dPBS. The cellpellet is then re-suspended in 10 mL dPBS, and the cells are countedwith a Coulter Z1 Dual Particle Counter (Beckman Coulter, Fullerton,Calif.). The cells are centrifuged again at 650×g for five minutes andre-suspended in stimulation buffer to an assay concentration of1.6×10⁶-2.8×10⁶ cells/mL.

The test compound is initially dissolved to a concentration of 400 μM indilution buffer (dPBS supplemented with 1 mg/mL BSA (0.1%)), and thenserially diluted with dilution buffer to final molar concentrationsranging from 100 μM to 0.1 nM. Oxotremorine is diluted in a similarmanner.

To measure oxotremorine inhibition of adenylyl cyclase (AC) activity, 25μL forskolin (25 μM final concentration diluted in dPBS), 25 μL dilutedoxotremorine, and 50 μL cells are added to agonist assay wells. Tomeasure the ability of a test compound to block oxotremorine-inhibitedAC activity, 25 μL forskolin and oxotremorine (25 μM and 5 μM finalconcentrations, respectively, diluted in dPBS) 25 μL diluted testcompound, and 50 μL cells are added to remaining assay wells.

Reactions are incubated for 10 minutes at 37° C. and stopped by additionof 100 μL ice-cold detection buffer. Plates are sealed, incubatedovernight at room temperature and counted the next morning on aPerkinElmer TopCount liquid scintillation counter (PerkinElmer Inc.,Wellesley, Mass.). The amount of cAMP produced (pmol/well) is calculatedbased on the counts observed for the samples and cAMP standards, asdescribed in the manufacturer's user manual. Data are analyzed bynonlinear regression analysis with the GraphPad Prism Software package(GraphPad Software, Inc., San Diego, Calif.) using the non-linearregression, one-site competition equation. The Cheng-Prusoff equation isused to calculate the K_(i), using the EC₅₀ of the oxotremorineconcentration-response curve and the oxotremorine assay concentration asthe K_(D) and [L], respectively. The K_(i) values are converted topK_(i) values to determine the geometric mean and 95% confidenceintervals. These summary statistics are then converted back to K_(i)values for data reporting.

In this assay, a lower K_(i) value indicates that the test compound hasa higher functional activity at the receptor tested. Compounds of theinvention are expected to have a K_(i) value of less than about 10 nMfor blockade of oxotremorine-inhibition of forskolin-mediated cAMPaccumulation in CHO-K1 cells expressing the hM₂ receptor, when tested inthis or a similar assay.

Blockade of Agonist-Mediated [³⁵S]GTPγS Binding

In a second functional assay, the functional potency of test compoundscan be determined by measuring the ability of the compounds to blockoxotremorine-stimulated [³⁵S]GTPγS binding in CHO-K1 cells expressingthe hM₂ receptor.

At the time of use, frozen membranes are thawed and then diluted inassay buffer with a final target tissue concentration of 5-10 μg proteinper well. The membranes are briefly homogenized using a Polytron PT-2100tissue disrupter and then added to the assay plates.

The EC₉₀ value (effective concentration for 90% maximal response) forstimulation of [³⁵S]GTPγS binding by the agonist oxotremorine isdetermined in each experiment.

To determine the ability of a test compound to inhibitoxotremorine-stimulated [³⁵S]GTPγS binding, the following is added toeach well of 96 well plates: 25 μL of assay buffer with [³⁵S]GTPγS (0.4nM), 25 μL of oxotremorine(EC₉₀) and GDP (3 μM), 25 μL of diluted testcompound and 25 μL CHO cell membranes expressing the hM₂ receptor. Theassay plates are then incubated at 37° C. for 60 minutes. The assayplates are filtered over 1% BSA-pretreated GF/B filters using aPerkinElmer 96-well harvester. The plates are rinsed with ice-cold washbuffer for 3×3 seconds and then air or vacuum dried. Microscint-20scintillation liquid (50 μL) is added to each well, and each plate issealed and radioactivity counted on a topcounter (PerkinElmer). Data areanalyzed by nonlinear regression analysis with the GraphPad PrismSoftware package (GraphPad Software, Inc., San Diego, Calif.) using thenon-linear regression, one-site competition equation. The Cheng-Prusoffequation is used to calculate the K_(i), using the IC₅₀ values of theconcentration-response curve for the test compound and the oxotremorineconcentration in the assay as the K_(D) and [L], ligand concentration,respectively.

In this assay, a lower K_(i) value indicates that the test compound hasa higher functional activity at the receptor tested. Compounds of theinvention are expected to have a K_(i) value of less than about 10 nMfor blockade of oxotremorine-stimulated [³⁵S]GTPγS binding in CHO-K1cells expressing the hM₂ receptor, when tested in this or a similarassay.

Blockade of Agonist-Mediated Calcium Release Via FLIPR Assays

Muscarinic receptor subtypes (M₁, M₃ and M₅ receptors), which couple toG_(q) proteins, activate the phospholipase C (PLC) pathway upon agonistbinding to the receptor. As a result, activated PLC hydrolyzesphosphatyl inositol diphosphate (PIP₂) to diacylglycerol (DAG) andphosphatidyl-1,4,5-triphosphate (IP₃), which in turn generates calciumrelease from intracellular stores, i.e., endoplasmic and sarcoplasmicreticulum. The FLIPR (Molecular Devices, Sunnyvale, Calif.) assaycapitalizes on this increase in intracellular calcium by using a calciumsensitive dye (Fluo-4AM, Molecular Probes, Eugene, Oreg.) thatfluoresces when free calcium binds. This fluorescence event is measuredin real time by the FLIPR, which detects the change in fluorescence froma monolayer of cells cloned with human M₁ and M₃, and chimpanzee M₅receptors. Antagonist potency can be determined by the ability ofantagonists to inhibit agonist-mediated increases in intracellularcalcium.

For FLIPR calcium stimulation assays, CHO cells stably expressing thehM₁, hM₃ and cM₅ receptors are seeded into 96-well FLIPR plates thenight before the assay is done. Seeded cells are washed twice byCellwash (MTX Labsystems, Inc.) with FLIPR buffer (10 mM HEPES, pH 7.4,2 mM calcium chloride, 2.5 mM probenecid in Hank's Buffered SaltSolution (HBSS) without calcium and magnesium) to remove growth mediaand leaving 50 μL/well of FLIPR buffer. The cells are then incubatedwith 50 μL/well of 4 μM FLUO-4AM (a 2× solution was made) for 40 minutesat 37° C., 5% carbon dioxide. Following the dye incubation period, cellsare washed two times with FLIPR buffer, leaving a final volume of 50μL/well.

To determine antagonist potency, the dose-dependent stimulation ofintracellular Ca²⁺ release for oxotremorine is first determined so thatantagonist potency can later be measured against oxotremorinestimulation at an EC₉₀ concentration. Cells are first incubated withcompound dilution buffer for 20 minutes, followed by agonist addition,which is performed by the FLIPR. An EC₉₀ value for oxotremorine isgenerated according to the method detailed in the FLIPR measurement anddata reduction section below, in conjunction with the formulaEC_(F)=((F/100−F)^1/H)*EC₅₀. An oxotremorine concentration of 3×EC_(F)is prepared in stimulation plates such that an EC₉₀ concentration ofoxotremorine is added to each well in the antagonist inhibition assayplates.

The parameters used for the FLIPR are: exposure length of 0.4 seconds,laser strength of 0.5 watts, excitation wavelength of 488 nm, andemission wavelength of 550 nm. Baseline is determined by measuring thechange in fluorescence for 10 seconds prior to addition of agonist.Following agonist stimulation, the FLIPR continuously measured thechange of fluorescence every 0.5 to 1 second for 1.5 minutes to capturethe maximum fluorescence change. The change of fluorescence is expressedas maximum fluorescence minus baseline fluorescence for each well. Theraw data is analyzed against the logarithm of drug concentration bynonlinear regression with GraphPad Prism (GraphPad Software, Inc., SanDiego, Calif.) using the built-in model for sigmoidal dose-response.Antagonist K_(i) values are determined by Prism using the oxotremorineEC₅₀ value as the K_(D) and the oxotremorine EC₉₀ for the ligandconcentration according to the Cheng-Prusoff equation (Cheng & Prusoff,1973).

In this assay, a lower K_(i) value indicates that the test compound hasa higher functional activity at the receptor tested. Compounds of theinvention are expected to have a K_(i) value of less than about 10 nMfor blockade of agonist-mediated calcium release in CHO cells stablyexpressing the hM₃ receptor, when tested in this or a similar assay.

Assay 3 Determination of Duration of Bronchoprotection in Guinea PigModel of Acetylcholine-Induced Bronchoconstriction

This in vivo assay is used to assess the bronchoprotective effects oftest compounds exhibiting muscarinic receptor antagonist activity.Groups of six male guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan,Madison, Wis.) weighing between 250 and 350 g are individuallyidentified by cage cards. Throughout the study animals are allowedaccess to food and water ad libitum.

Test compounds are administered via inhalation over 10 minutes in awhole-body exposure dosing chamber (R&S Molds, San Carlos, Calif.). Thedosing chambers are arranged so that an aerosol was simultaneouslydelivered to 6 individual chambers from a central manifold. Guinea pigsare exposed to an aerosol of a test compound or vehicle (WFI). Theseaerosols are generated from aqueous solutions using an LC Star NebulizerSet (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, Va.)driven by a mixture of gases (CO₂=5%, O₂=21% and N₂=74%) at a pressureof 22 psi. The gas flow through the nebulizer at this operating pressureis approximately 3 L/minute. The generated aerosols are driven into thechambers by positive pressure. No dilution air is used during thedelivery of aerosolized solutions. During the 10 minute nebulization,approximately 1.8 mL of solution is nebulized. This is measuredgravimetrically by comparing pre-and post-nebulization weights of thefilled nebulizer.

The bronchoprotective effects of test compounds administered viainhalation are evaluated using whole body plethysmography at 1.5, 24, 48and 72 hours post-dose. Forty-five minutes prior to the start of thepulmonary evaluation, each guinea pig is anesthetized with anintramuscular injection of ketamine (43.75 mg/kg), xylazine (3.50 mg/kg)and acepromazine (1.05 mg/kg). After the surgical site is shaved andcleaned with 70% alcohol, a 2-3 cm midline incision of the ventralaspect of the neck was made. Then, the jugular vein is isolated andcannulated with a saline-filled polyethylene catheter (PE-50, BectonDickinson, Sparks, Md.) to allow for intravenous infusions of ACh(Sigma-Aldrich, St. Louis, Mo.) in saline. The trachea is then dissectedfree and cannulated with a 14G teflon tube (#NE-014, Small Parts, MiamiLakes, Fla.). If required, anesthesia is maintained by additionalintramuscular injections of the aforementioned anesthetic mixture. Thedepth of anesthesia is monitored and adjusted if the animal responds topinching of its paw or if the respiration rate is greater than 100breaths/minute.

Once the cannulations are complete, the animal is placed into aplethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, Conn.) and anesophageal pressure cannula (PE-160, Becton Dickinson, Sparks, Md.) isinserted to measure pulmonary driving pressure (pressure). The teflontracheal tube is attached to the opening of the plethysmograph to allowthe guinea pig to breathe room air from outside the chamber. The chamberis then sealed. A heating lamp is used to maintain body temperature andthe guinea pig's lungs are inflated 3 times with 4 mL of air using a 10mL calibration syringe (#5520 Series, Hans Rudolph, Kansas City, Mo.) toensure that the lower airways do not collapse and that the animal doesnot suffer from hyperventilation.

Once it is determined that baseline values are within the range 0.3-0.9mL/cm H₂O for compliance and within the range 0.1-0.199 cm H₂O/mL persecond for resistance, the pulmonary evaluation is initiated. A Buxcopulmonary measurement computer program enables the collection andderivation of pulmonary values.

Starting this program initiates the experimental protocol and datacollection. The changes in volume over time that occur within theplethysmograph with each breath are measured via a Buxco pressuretransducer. By integrating this signal over time, a measurement of flowis calculated for each breath. This signal, together with the pulmonarydriving pressure changes, which are collected using a Sensym pressuretransducer (#TRD4100), is connected via a Buxco (MAX 2270) preamplifierto a data collection interface (#'s SFT3400 and SFT3813). All otherpulmonary parameters are derived from these two inputs.

Baseline values are collected for 5 minutes, after which time the guineapigs are challenged with ACh. ACh (0.1 mg/mL) is infused intravenouslyfor 1 minute from a syringe pump (sp210iw, World Precision Instruments,Inc., Sarasota, Fla.) at the following doses and prescribed times fromthe start of the experiment: 1.9 μg/minute at 5 minutes, 3.8 μg/minuteat 10 minutes, 7.5 μg/minute at 15 minutes, 15.0 μg/minute at 20minutes, 30 μg/minute at 25 minutes and 60 μg/minute at 30 minutes. Ifresistance or compliance has not returned to baseline values at 3minutes following each ACh dose, the guinea pig's lungs are inflated 3times with 4 mL of air from a 10 mL calibration syringe. Recordedpulmonary parameters includes respiration frequency (breaths/minute),compliance (mL/cm H₂O) and pulmonary resistance (cm H₂O/mL per second).Once the pulmonary function measurements are completed at minute 35 ofthis protocol, the guinea pig is removed from the plethysmograph andeuthanized by carbon dioxide asphyxiation.

The data are evaluated in one or both of the following ways:

(a) Pulmonary resistance (R_(L), cm H₂O/mL per second) is calculatedfrom the ratio of “change in pressure” to “the change in flow.” TheR_(L) response to ACh (60 μg/min, IH) is computed for the vehicle andthe test compound groups. The mean ACh response in vehicle-treatedanimals, at each pre-treatment time, is calculated and used to compute %inhibition of ACh response, at the corresponding pre-treatment time, ateach test compound dose. Inhibition dose-response curves for ‘R_(L)’ arefitted with a four parameter logistic equation using GraphPad Prism,version 3.00 for Windows (GraphPad Software, San Diego, Calif.) toestimate bronchoprotective ID₅₀ (dose required to inhibit the ACh (60μg/min) bronchoconstrictor response by 50%). The equation used is asfollows:Y=Min+(Max−Min)/(1+10^(((log ID50−X)*Hillslope)))where X is the logarithm of dose, Y is the response (% Inhibition of AChinduced increase in R_(L)). Y starts at Min and approachesasymptotically to Max with a sigmoidal shape.

(b) The quantity PD₂, which is defined as the amount of ACh or histamineneeded to cause a doubling of the baseline pulmonary resistance, iscalculated using the pulmonary resistance values derived from the flowand the pressure over a range of ACh or histamine challenges using thefollowing equation (which is derived from a equation used to calculatePC₂₀ values described in American Thoracic Society. Guidelines formethacholine and exercise challenge testing—1999. Am J Respir Crit CareMed. 161:309-329 (2000)):

${PD}_{2} = {{antilog}\;\left\lbrack {{\log\; C_{1}} + \frac{\left( {{\log\; C_{2}} - {\log\; C_{1}}} \right)\left( {{2R_{0}} - R_{1}} \right)}{R_{2} - R_{1}}} \right\rbrack}$where: C₁ is the concentration of ACh or histamine preceding C₂; C₂ isthe concentration of ACh or histamine resulting in at least a 2-foldincrease in pulmonary resistance (R_(L)); R₀ is the baseline R_(L)value; R₁ is the R_(L) value after C₁; and R₂ is the R_(L) value afterC₂. An efficacious dose is defined as a dose that limits thebronchrestriction response to a 50 μg/mL dose of ACh to a doubling ofthe baseline pulmonary resistance (PD₂₍₅₀₎).

Statistical analysis of the data is performed using a two-tailedStudents t-test. A P-value <0.05 is considered significant. Generally,test compounds having a PD₂₍₅₀₎ less than about 200 μg/mL forACh-induced bronchoconstriction at 1.5 hours post-dose in this assay arepreferred. Compounds of the invention are expected to have a PD₂₍₅₀₎ ofless than about 200 μg/mL for ACh-induced bronchoconstriction at 1.5hours post-dose, when tested in this or a similar assay.

Assay 4 Inhalation Guinea Pig Salivation Assay

Guinea pigs (Charles River, Wilmington, Mass.) weighing 200-350 g areacclimated to the in-house guinea pig colony for at least 3 daysfollowing arrival. Test compound or vehicle are dosed via inhalation(IH) over a 10 minute time period in a pie shaped dosing chamber (R&SMolds, San Carlos, Calif.). Test solutions are dissolved in sterilewater and delivered using a nebulizer filled with 5.0 mL of dosingsolution. Guinea pigs are restrained in the inhalation chamber for 30minutes. During this time, guinea pigs are restricted to an area ofapproximately 110 sq. cm. This space is adequate for the animals to turnfreely, reposition themselves, and allow for grooming. Following 20minutes of acclimation, guinea pigs are exposed to an aerosol generatedfrom a LS Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment,Inc. Midlothian, Va.) driven by house air at a pressure of 22 psi. Uponcompletion of nebulization, guinea pigs are evaluated at 1.5, 6, 12, 24,48, or 72 hrs after treatment. Guinea pigs are anesthetized one hourbefore testing with an intramuscular (IM) injection of a mixture ofketamine 43.75 mg/kg, xylazine 3.5 mg/kg, and acepromazine 1.05 mg/kg atan 0.88 mL/kg volume. Animals are placed ventral side up on a heated(37° C.) blanket at a 20 degree incline with their head in a downwardslope. A 4-ply 2×2 inch gauze pad (Nu-Gauze General-use sponges, Johnsonand Johnson, Arlington, Tex.) is inserted in the guinea pig's mouth.Five minutes later, the muscarinic agonist pilocarpine (3.0 mg/kg, SC)is administered and the gauze pad is immediately discarded and replacedby a new pre-weighed gauze pad. Saliva is collected for 10 minutes, atwhich point the gauze pad is weighed and the difference in weightrecorded to determine the amount of accumulated saliva (in mg). The meanamount of saliva collected for animals receiving the vehicle and eachdose of test compound is calculated. The vehicle group mean isconsidered to be 100% salivation. Results are calculated using resultmeans (n=3 or greater). Confidence intervals (95%) are calculated foreach dose at each time point using two-way ANOVA. This model is amodified version of the procedure described in Rechter, “Estimation ofanticholinergic drug effects in mice by antagonism againstpilocarpine-induced salivation” Ata Pharmacol Toxicol 24:243-254 (1996).

The mean weight of saliva in vehicle-treated animals, at eachpre-treatment time, is calculated and used to compute % inhibition ofsalivation, at the corresponding pre-treatment time, at each dose. Theinhibition dose-response data are fitted to a four parameter logisticequation using GraphPad Prism, version 3.00 for Windows (GraphPadSoftware, San Diego, Calif.) to estimate anti-sialagogue ID₅₀ (doserequired to inhibit 50% of pilocarpine-evoked salivation). The followingequation is used:Y=Min+(Max−Min)/(1+10^(((log ID50−X)*Hillslope)))where X is the logarithm of dose, Y is the response (% inhibition ofsalivation). Y starts at Min and approaches asymptotically to Max with asigmoidal shape. The ratio of the anti-sialagogue ID₅₀ tobronchoprotective ID₅₀ is used to compute the apparent lung-selectivityindex of the test compound. Generally, compounds having an apparentlung-selectivity index greater than about 5 are preferred. Compounds ofthe invention are expected to have an apparent lung-selectivity indexgreater than 5, when tested in this or a similar assay.

Assay 5 Methacholine-Induced Depressor Responses in Conscious GuineaPigs

Healthy, adult, male Sprague-Dawley guinea pigs (Harlan, Indianapolis,Ind.), weighing between 200 and 300 g are used in these studies. Underisoflurane anesthesia (to effect), animals are instrumented with commoncarotid artery and jugular vein catheters (PE-50 tubing). The cathetersare exteriorized utilizing a subcutaneous tunnel to the subscapulararea. All surgical incisions are sutured with 4-0 Ethicon Silk and thecatheters locked with heparin (1000 units/mL). Each animal isadministered saline (3 mL, SC) at the end of surgery as well asbuprenorphine (0.05 mg/kg, IM). Animals are allowed to recover on aheating pad before being returned to their holding rooms.

Approximately 18 to 20 hours following surgery, the animals are weighedand the carotid artery catheter on each animal is connected to atransducer for recording arterial pressure. Arterial pressure and heartrate are recorded using a Biopac MP-100 Acquisition System. Animals areallowed to acclimate and stabilize for a period of 20 minutes.

Each animal is challenged with MCh (0.3 mg/kg, IV) administered throughthe jugular venous line and the cardiovascular response is monitored for10 minutes. The animals are then placed into the whole body dosingchamber, which is connected to a nebulizer containing the test compoundor vehicle solution. The solution is nebulized for 10 minutes using agas mixture of breathable air and 5% carbon dioxide with a flow rate of3 liters/minute. The animals are then removed from the whole bodychamber and returned to their respective cages. At 1.5 and 24 hourspost-dosing, the animals are re-challenged with MCh (0.3 mg/kg, IV) andthe hemodynamic response is determined. Thereafter, the animals areeuthanized with sodium pentobarbital (150 mg/kg, IV).

MCh produces a decrease in mean arterial pressure (MAP) and decrease inheart rate (bradycardia). The peak decrease, from baseline, in MAP(depressor responses) is measured for each MCh challenge (before andafter IH dosing). The effects of treatment on the MCh responses areexpressed as % inhibition (mean+/−SEM) of the control depressorresponses. Two-way ANOVA with the appropriate post-hoc test is used totest the effects of treatment and pre-treatment time. The depressorresponses to MCh are expected to be relatively unchanged at 1.5 and 24hours after inhalation dosing with vehicle. The ratio of theanti-depressor ID₅₀ to bronchoprotective ID₅₀ is used to computeapparent lung-selectivity of the test compound. Generally, compoundshaving an apparent lung-selectivity index greater than 5 are preferred.It is expected that the compounds of the invention will exhibit anapparent lung-selectivity index greater than 5, when tested in this or asimilar assay.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

1. A compound of formula Ia:

wherein: a is 0 or an integer of from 1 to 5; each R¹ is independentlyselected from (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl,(3-6C)cycloalkyl, cyano, halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g),—NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j),and R^(1k) is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;b is 0 or an integer of from 1 to 4; each R² is independently selectedfrom (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano,halo, —OR^(2a), —C(O)OR^(2b), —SR^(2c), —S(O)R^(2d), —S(O)₂R^(2e),—NR^(2f)R^(2g), —NR^(2h)S(O)₂R^(2i), and —NR^(2j)C(O)R^(2k); where eachof R^(2a), R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h),R^(2i),R^(2j), and R^(2k) is independently hydrogen, (1-4C)alkyl orphenyl(1-4C)alkyl; W represents O or NW^(a), where W^(a) is hydrogen or(1-4C)alkyl; c is 0 or an integer from 1 to 5; each R³ independentlyrepresents (1-4C)alkyl or two R³ groups are joined to form(1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl; m is 0 or 1; R⁴ isselected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; n is 0 or 1;Ar¹ represents a phenylene group substituted with (R⁵)_(p) where p is 0or an integer from 1 to 4 and each R⁵ is independently selected fromhalo, hydroxy, (1-4C)alkyl, and (1-4C)alkoxy; q is 0 or 1; R⁶ isselected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; r is 0, 1 or2; R⁷ is selected from hydrogen, (1-4C)alkyl, (3-4C)cycloalkyl,—C(O)(1-4C)alkyl, -(1-4C)alkyleneC(O)OR^(7a), —C(O)heterocyclyl,—C(O)CH(NH₂)(1-4C)alkyleneQ, -(1-4C)alkyleneC(O)Q′,—C(O)(1-4C)alkyleneQ′, and —S(O)₂(1-4C)alkyleneQ′; where Q is anitrogen-containing substituent selected from —NR^(7b)R^(7c) andheteroaryl; Q′ is a nitrogen-containing substituent selected from—NR^(7d)R^(7e) and heterocyclyl; R^(7a) is hydrogen or (1-4C)alkyl; eachof R^(7b), R^(7c), R^(7d) and R^(7e) independently represents hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl or hydroxyphenyl, and where (1-4C)alkyl isunsubstituted or substituted by 1 or 2 substituents independentlyselected from amido, cyano, furyl, hydroxyl, and methylimidazolyl; theheterocyclyl contains 1 or 2 nitrogen atoms, and is unsubstituted orsubstituted by 1 or 2 substituents independently selected from hydroxyl,amido, (1-4C)alkoxy, oxo, —S(O)₂(1-4C)alkyl, —(CH₂)O(1-4C)alkyl,-(1-4C)alkyleneOH, —NR^(7f)R^(7g) and —C(O)NR^(7h)R^(7i), where each ofR^(7f), R^(7g) R^(7h) and R^(7i) independently represents hydrogen or(1-4C)alkyl; and the heteroaryl contains 1 or 2 nitrogen atoms; X¹ isselected from (1-3C)alkylene, —C(O)(1-3C)alkylene, (1-3C)alkyleneC(O)—,—SO₂—, —SO₂(1-3C)alkylene and (1-3C)alkyleneSO₂—; where the alkylenegroup in any X¹ is optionally substituted with 1 or 2 substituentsindependently selected from (1-4C)alkyl and —NR^(Xa)R^(Xb); whereinR^(Xa) and R^(Xb) are independently selected from hydrogen and(1-4alkyl); s is 0, 1 or 2; each R⁸ independently represents(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano,nitro, halo, N,N-di(1-4C)alkylamino(2-4C)alkoxy, —OR^(8a), —C(O)OR^(8b),—SR^(8c), —S(O)R^(8d), —S(O)₂R^(8e) or —NR^(8f)R^(8g); each of R^(8a),R^(8b), R^(8c), R^(8d), R^(8e), R^(8f) and R^(8g) is independentlyhydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, phenyl or phenyl(1-4C)alkyl,wherein each phenyl group is unsubstituted or substituted by 1 or 2substituents independently selected from halo, (1-4C)alkyl and(1-4C)alkoxy; R⁹ is selected from hydrogen, (1-4C)alkyl,(1-4C)alkyleneNR^(9a)R^(9b), and phenyl, each of R^(9a) and R^(9b) isindependently hydrogen or (1-4C)alkyl; or R⁹ is taken together with R⁸to form a ring having 1 to 2 oxygen atoms, where said ring isunsubstituted or substituted by 1 or 2 (1-4C)alkyl substituents; andwherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,R⁵, R⁸, R^(8a-8g), R⁹, and R^(9a-9b) is optionally substituted with 1 to5 fluoro substituents; or a pharmaceutically acceptable salt or solvateor stereoisomer thereof.
 2. The compound of claim 1, wherein a, b and ceach represent
 0. 3. The compound of claim 1, wherein W represents O. 4.The compound of claim 1, wherein m is
 0. 5. The compound of claim 1,wherein n is
 0. 6. The compound of claim 1, wherein q is
 0. 7. Thecompound of claim 1, wherein r is
 1. 8. The compound of claim 1, whereinAr¹ represents phen-1,3-ylene.
 9. The compound of claim 8, wherein m, nand q are 0, and r is
 1. 10. The compound of claim 1, wherein R⁴ isselected from hydrogen and (1-4C)alkyl.
 11. The compound of claim 1,wherein R⁶ is hydrogen.
 12. The compound of claim 1, wherein R⁷ ishydrogen.
 13. The compound of claim 1, wherein X¹ is (1-3C)alkylene. 14.The compound of claim 1, wherein s is 0 or
 1. 15. The compound of claim14, wherein s is 1, and R⁸ is —OR^(8a), where R^(8a) is hydrogen. 16.The compound of claim 1, wherein R⁹ is selected from hydrogen and(1-4C)alkyl.
 17. A compound selected from: biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxy-3-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-[2-({3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-hydroxy-2-methoxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-(2-{3-[2-(2-hydroxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-(2-{3-[2-(4-methoxybenzylamino)ethylcarbamoyl]benzoylamino}ethyl)piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3-hydroxy-4-methoxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-[2-({3-[2-(3,4-dihydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; biphenyl-2-ylcarbamic acid1-{2-[(3-{2-[2-(4-hydroxyphenyl)ethylamino]ethylcarbamoyl}benzoyl)methylamino]ethyl}piperidin-4-ylester; or a pharmaceutically acceptable salt or solvate thereof.
 18. Thecompound of claim 17, selected from: biphenyl-2-ylcarbamic acid1-[2-({3-[2-(4-hydroxybenzylamino)ethylcarbamoyl]benzoyl}methylamino)ethyl]piperidin-4-ylester; or a pharmaceutically acceptable salt or solvate thereof.
 19. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1or
 17. 20. A process for preparing the compound of claim 1, comprising:(a) reacting a compound of formula II:

or a salt thereof, with a compound of formula III:

wherein L¹ represents a leaving group; or (b′) coupling a compound offormula IVb:

with a compound of formula Vb:

or a reactive derivative thereof; or (c) coupling a compound of formulaVIa:

or a reactive derivative thereof, with a compound of formula VIIa:

or (d) reacting a compound of formula VIII:

wherein L² represents a leaving group, with a compound of formula IX:H—Y  IX or (e) reacting a compound of formula II with a compound offormula X:

in the presence of a reducing agent; or (f) reacting a compound offormula XI:

with a compound of formula IX in the presence of a reducing agent; andthen (g) removing any protecting groups that may be present to provide acompound of formula Ia; wherein Z¹ is —N(R⁴)C(O)—; Z² is —C(O)N(R⁶)—,and Y is:


21. The process of claim 20, which further comprises forming apharmaceutically acceptable salt of the compound of formula Ia.